Mixed host co-assembled systems for broad-scope analyte sensing.

Here we report a systems chemistry oriented approach for developing information-rich mixed host chemosensors. We show that co-assembling macrocyclic hosts from different classes, DimerDye sulfonatocalix[4]arenes and cucurbit[n]urils, effectively increases the scope of analyte binding interactions and therefore, sensory outputs. This simple dynamic strategy exploits cross-reactive noncovalent host-host complexation interactions while integrating a reporter dye, thereby producing emergent photophysical responses when an analyte interacts with either host. We first demonstrate the advantages of mixed host co-assembled chemosensors through an increased detection range of hydrophobic, cationic, neutral, and anionic drugs. We then implement mixed host sensors in an array-based platform for the differentiation of illicit drugs, including cannabinoids, benzodiazepine analogs, opiates, anesthetics, amphetamine, and common adulterating substances. Finally, the potential of this approach is applied to profiling real-world multi-component illicit street drug samples, proving to be more effective than classical sensor arrays.

Surface populations as a model for the distance-dependence of the interfacial refractive index.

Vibrational sum frequency spectra provide information about interfaces that is sensitive to the orientation of molecules, their electronic environment, and the local electric fields. Here, we use molecular dynamics simulations in order to study a surfactant, para-cyanophenol, at the air-water interface. The volume fractions of water and the organic surfactant are considered at various points over the nanometer-scale region in a Lorentz-Lorenz model. We find that the calculated ratios of nonlinear susceptibility tensor elements are in agreement with experimental data only when this depth profile was considered. We also use these data to evaluate the ratio of the C-N hyperpolarizability tensor elements in the interfacial region.

Phase of the second-order susceptibility in vibrational sum frequency generation spectroscopy: Origins, utility, and measurement techniques.

Vibrational sum frequency generation can provide valuable structural information at surfaces and buried interfaces. Relating the measured spectra to the complex-valued second-order susceptibility χ(2) is at the heart of the technique and a requisite step in nearly all subsequent analyses. The magnitude and phase of χ(2) as a function of frequency reveal important information about molecules and materials in regions where centrosymmetry is broken. In this tutorial-style perspective, the origins of the χ(2) phase are first described, followed by the utility of phase determination. Finally, some practical methods of phase extraction are discussed.

Trace Detection of Adulterants in Illicit Opioid Samples Using Surface-Enhanced Raman Scattering and Random Forest Classification.

The detection of trace adulterants in opioid samples is an important aspect of drug checking, a harm reduction measure that is required as a result of the variability and unpredictability of the illicit drug supply. While many analytical methods are suitable for such analysis, community-based approaches require techniques that are amenable to point-of-care applications with minimal sample preparation and automated analysis. We demonstrate that surface-enhanced Raman spectroscopy (SERS), combined with a random forest classifier, is able to detect the presence of two common sedatives, bromazolam (0.32-36% w/w) and xylazine (0.15-15% w/w), found in street opioid samples collected as a part of a community drug checking service. The Raman predictions, benchmarked against mass spectrometry results, exhibited high specificity (88% for bromazolam, 96% for xylazine) and sensitivity (88% for bromazolam, 92% for xylazine) for the compounds of interest. We additionally provide evidence that this exceeds the performance of a more conventional approach using infrared spectral data acquired on the same samples. This demonstrates the feasibility of SERS for point-of-care analysis of challenging multicomponent samples containing trace adulterants.

Variable-Angle Surface Spectroscopy Reveals the Water Structure in the Stern Layer at Charged Aqueous Interfaces.

At charged aqueous interfaces, the second-order nonlinear optical response originates from water molecules within the diffuse part of the electrical double layer, which are ordered by the surface field and from water that additionally experiences chemical and physical interactions with the surface in the Stern layer. These two environments can either reinforce or diminish the overall signal and can be disentangled by varying the coherence length of their interaction with external laser fields. Here, we demonstrate a method in which the angle of incidence is varied to afford a significant change in the coherence length. When this technique was applied to the silica-water interface, it was observed that water molecules in the Stern and diffuse layers direct their hydrogen atoms toward the mineral surface at a low ionic strength and neutral pH. A decrease in the signal with increasing ionic strength is attributed to hydrated cation adsorption that competes with free water for deprotonated silanol sites.

Beyond a spec: assessing heterogeneity in the unregulated opioid supply.

BACKGROUND: Drug checking services aim to provide compositional information for the illicit drug supply and are being employed in public health responses to extreme rates of overdose associated with fentanyl within street opioids. The technologies used within these services range from basic qualitative tests, such as immunoassay test strips, to comprehensive quantitative analyses, such as mass spectrometry. In general, there is concern that heterogeneity of a drug mixture adds significant uncertainty when using drug checking results based on a small subsamples. The presence of hot spots of active drug components in this context is often termed the 'chocolate chip cookie effect'. Establishing the limitations of the service are essential for interpretation of the results. METHODS: This study assesses the consequence of drug heterogeneity and sampling of consumer level opioid purchased in Victoria, British Columbia ( n = 21 , 50-100 mg each) on quantitative fentanyl results determined from testing with paper spray mass spectrometry. RESULTS: Using descriptive statistics, such as relative standard deviation and interquartile range, the results demonstrate varied distributions of fentanyl concentrations within a single drug batch. However, the presence of hot spots, defined as outliers, were relatively rare. CONCLUSIONS: This study found that the variability in fentanyl concentration from drug heterogeneity and sampling is greater than that attributed to the analytical technique. On a practical level, this provides data to help guide communication of limitations of drug checking services, supporting the aim of trust and transparency between services and people who use drugs. However, if drug checking services continue to be restricted from fully engaging with the reality of manufacturing, buying, selling, mixing and dosing practices, the accuracy, usefulness, and impact will always be limited.

Surface Structural Changes in Silicone Rubber Due to Electrical Tracking.

There is a growing interest in the use of silicone composite insulators for electrical power transmission and distribution applications. However, such materials are susceptible to degradation as they are exposed to electrical and environmental stresses during operating conditions. Therefore, it is crucial to gain a thorough understanding of the degradation mechanism through changes in the material structure that may provide insight into potential failures in the electrical grid. Attenuated total reflection Fourier transform infrared spectroscopy and two-dimensional correlation spectroscopy (2D-COS) were used along with contact angle measurements to characterize changes in silicone rubber samples from actual insulators subjected to tracking wheel testing. The results showed a decrease in absorbance of different infrared bands representing different functional groups, such as Si-O-Si, methyl functional groups, and both Al-O and hydroxyl groups of alumina trihydrate as a function of the number of tracking cycles. The sequence of changes in the functional groups was determined by 2D-COS as Al-O and OH followed by Si-O-Si polymer backbone modes, followed by polymer methyl side chains. An enhancement in the average contact angle with the number of tracking cycles revealed a concomitant increase in surface roughness with electrical tracking.

Toward automated infrared spectral analysis in community drug checking.

The body of knowledge surrounding infrared spectral analysis of drug mixtures continues to grow alongside the physical expansion of drug checking services. Technicians trained in the analysis of spectroscopic data are essential for reasons that go beyond the accuracy of the analytical results. Significant barriers faced by people who use drugs in engaging with drug checking services include the speed and accuracy of the results, and the availability and accessibility of the service. These barriers can be overcome by the automation of interpretations. A random forest model for the detection of two compounds, MDA and fluorofentanyl, was trained and optimized with drug samples acquired at a community drug checking site. This resulted in a 79% true positive and 100% true negative rate for MDA, and 61% true positive and 97% true negative rate for fluorofentanyl. The trained models were applied to selected drug samples to demonstrate a proposed workflow for interpreting and validating model predictions. The detection of MDA was demonstrated on three mixtures: (1) MDMA and MDA, (2) MDA and dimethylsulfone, and (3) fentanyl, etizolam, and benzocaine. The classification of fluorofentanyl was applied to a drug mixture containing fentanyl, fluorofentanyl, 4-anilino-N-phenethylpiperidine, caffeine, and mannitol. Feature importance was calculated using shapely additive explanations to better explain the model predictions and k-nearest neighbors was used for visual comparison to labelled training data. This is a step toward building appropriate trust in computer-assisted interpretations in order to promote their use in a harm reduction context.

A strategy for the detection of benzodiazepine drugs using low-resolution paper-spray mass spectrometry for harm reduction drug checking.

The ability to detect newly emerging substances is of great importance in reducing harms for people who use drugs. New psychoactive substances including novel benzodiazepines in the illicit drug supply have been linked to high rates of overdose deaths while complicating drug checking as an overdose prevention strategy. Paper-spray mass spectrometry (PS-MS) has emerged as a novel strategy to rapidly detect trace components in street drug samples. While targeted, low-resolution PS-MS methods have proven effective, newly emerging substances are often missed. To address this, a method was applied to low-resolution full-scan PS-MS data to aid in the early detection and identification of novel benzodiazepines in the unregulated drug supply. Using the developed method, true positives rates of 0.89 and 0.75 were achieved for bromazolam and etizolam in street samples obtained in a community drug checking service. The applicability of the method was further demonstrated for a novel benzodiazepine, desalkylgidazepam, that has recently emerged in the illicit drug supply.

Development of a neural network model to predict the presence of fentanyl in community drug samples.

INTRODUCTION: Increasingly, Fourier-transform infrared (FTIR) spectroscopy is being used as a harm reduction tool to provide people who use drugs real-time information about the contents of their substances. However, FTIR spectroscopy has been shown to have a high detection limit for fentanyl and interpretation of results by a technician can be subjective. This poses concern, given that some synthetic opioids can produce serious toxicity at sub-detectable levels. The objective of this study was to develop a neural network model to identify fentanyl and related analogues more accurately in drug samples compared to traditional analysis by technicians. METHODS: Data were drawn from samples analyzed point-of-care using combination FTIR spectroscopy and fentanyl immunoassay strips in British Columbia between August 2018 and January 2021. We developed neural network models to predict the presence of fentanyl based on FTIR data. The final model was validated against the results from immunoassay strips. Prediction performance was assessed using F1 score, accuracy, and area under the receiver-operating characteristic curve (AUROC), and was compared to results obtained from analysis by technicians. RESULTS: A total of 12,684 samples were included. The neural network model outperformed results from those analyzed by technicians, with an F1 score of 96.4% and an accuracy of 96.4%, compared to 78.4% and 82.4% with a technician, respectively. The AUROC of the model was 99.0%. Fentanyl positive samples correctly detected by the model but not by the technician were typically those with low fentanyl concentrations (median: 2.3% quantity by weight; quartile 1-3: 0.0%-4.6%). DISCUSSION: Neural network models can accurately predict the presence of fentanyl and related analogues using FTIR data, including samples with low fentanyl concentrations. Integrating this tool within drug checking services utilizing FTIR spectroscopy has the potential to improve decision making to reduce the risk of overdose and other negative health outcomes.

Second-Order Nonlinear Optics as an Orientation-Independent Probe of Molecular Environments at Interfaces.

Measurement techniques that probe the second-order susceptibility, such as second-harmonic and sum-frequency generation, are recognized for their ability to study environments with broken centrosymmetry. As a result, they serve as reporters of molecules at surfaces because the second-order susceptibility is often zero in the adjacent bulk media. Although the signals measured in such experiments carry unique information about the interfacial environment, the challenge is to disentangle properties related to the electronic structure as they are wrapped up in the orientation distribution. Over the past 30 years, this challenge has been turned into an opportunity, as many studies have sought to learn about the arrangement of molecules at surfaces. Here we demonstrate that the flipped case is possible, where fundamental properties of the interfacial environment can be extracted in a manner that is completely independent of, and therefore oblivious to, the orientation distribution. Using p-cyanophenol adsorbed at the air-water interface as an example, we illustrate that the cyano group polarizability varies less along the direction of the C-N bond when at the surface than when the same molecules are in the bulk aqueous phase.

Point-of-care community drug checking technologies: an insider look at the scientific principles and practical considerations.

Drug checking is increasingly being explored outside of festivals and events to be an ongoing service within communities, frequently integrated within responses to illicit drug overdose. The choice of instrumentation is a common question, and the demands on these chemical analytical instruments can be challenging as illicit substances may be more complex and include highly potent ingredients at trace levels. The answer remains nuanced as the instruments themselves are not directly comparable nor are the local demands on the service, meaning implementation factors heavily influence the assessment and effectiveness of instruments. In this perspective, we provide a technical but accessible introduction to the background of a few common drug checking methods aimed at current and potential drug checking service providers. We discuss the following tools that have been used as part of the Vancouver Island Drug Checking Project in Victoria, Canada: immunoassay test strips, attenuated total reflection IR-absorption spectroscopy, Raman spectroscopy from powder samples, surface-enhanced Raman scattering in a solution of colloidal gold nanoparticles, and gas chromatography-mass spectrometry. Using four different drug mixtures received and tested at the service, we illustrate the strengths, limitations, and capabilities of such instruments, and expose the scientific theory to give further insight into their analytical results. Each case study provides a walk-through-style analysis for a practical comparison between data from several different instruments acquired on the same sample. Ideally, a single instrument would be able to achieve all of the objectives of drug checking. However, there is no clear instrument that ticks every box; low cost, portable, rapid, easy-to-use and provides highly sensitive identification and accurate quantification. Multi-instrument approaches to drug checking may be required to effectively respond to increasingly complex and highly potent substances demanding trace level detection and the potential for quantification.

Carfentanil structural analogs found in street drugs by paper spray mass spectrometry and their characterization by high-resolution mass spectrometry.

Carfentanil is one of the most potent synthetic opioids ever developed, with an estimated analgesic potency approximately 20-100 times that of fentanyl and 10,000 times that of morphine. Carfentanil has been appearing in the illicit drug supply in many regions and has been linked to fatal overdose events. A subset of 59 street drug samples obtained in Victoria, B.C., that were confirmed to contain carfentanil were analyzed by mass spectrometry for this study. Carfentanil quantitation by paper spray mass spectrometry ranged from 0.05 to 2.95 w/w% (median = 0.32%) in the original drug sample. Paper spray mass spectrometry analysis also detected two unknown peaks at m/z 380.2 and 381.2 in 31 of these 59 samples (53%). Initial tandem mass spectrometry experiments revealed structural similarities between these unknown compounds and carfentanil, suggesting they were potential structural analogs, possibly arising from incomplete purification during synthesis. High-resolution mass spectrometry determined the chemical formulas of these compounds as C23 H29 N3 O2 (m/z 380.2333) and C23 H29 N2 O3 (m/z 381.2137). Literature and tandem mass spectrometry results were used to determine the identity of these potential new psychoactive substances, C23 H29 N3 O2 as desmethylcarfentanil amide and C23 H29 N2 O3 as desmethylcarfentanil acid. µ-Opioid receptor binding modeling determined that the binding poses of these analogs were nearly identical to that of carfentanil with relative binding energy calculations of 0.544 kJ/mol (desmethylcarfentanil amide) and -0.171 kJ/mol (desmethylcarfentanil acid); these data suggest they may share the toxic effects of carfentanil and have similar potencies.

Everywhere and for everyone: proportionate universalism as a framework for equitable access to community drug checking.

BACKGROUND: Illicit drug overdoses have reached unprecedented levels, exacerbated by the COVID-19 pandemic. Responses are needed that address the increasingly potent and unpredictable drug supply with better reach to a wide population at risk for overdose. Drug checking is a potential response offered mainly within existing harm reduction services, but strategies are needed to increase reach and improve equitable delivery of drug checking services. METHODS: The purpose of this qualitative study was to explore how to extend the reach of drug checking services to a wide population at risk of overdose. We conducted 26 in-depth interviews with potential service users to identify barriers to service use and strategies to increase equitable delivery of drug checking services. Our analysis was informed by theoretical perspectives on equity, and themes were developed relevant to equitable delivery through attention to quality dimensions of service use: accessibility, appropriateness, effectiveness, safety, and respect. RESULTS: Barriers to equitable service delivery included criminalization and stigma, geographic and access issues, and lack of cultural appropriateness that deter service use for a broad population with diverse needs. Strategies to enhance equitable access include 1ocating services widely throughout communities, integrating drug checking within existing health care services, reframing away from risk messaging, engaging peers from a broad range of backgrounds, and using discrete methods of delivery to help create safer spaces and better reach diverse populations at risk for overdose. CONCLUSIONS: We propose proportionate universalism in drug checking as a guiding framework for the implementation of community drug checking as an equity-oriented harm reduction intervention and as a population health response. Both a universal equity-oriented approach and multiple tailored approaches are required to facilitate drug checking services that maximize reach and appropriateness to respond to diverse needs.

Substance Use Stigma and Community Drug Checking: A Qualitative Study Examining Barriers and Possible Responses.

BACKGROUND: Community drug checking is an emerging response to the overdose crisis. However, stigma has been identified as a potential barrier to service use that requires investigation. METHODS: A qualitative study explored how best to implement drug checking services to the wider population including those at risk of overdose. A secondary analysis of 26 interviews with potential service users examine how stigma may be a barrier to service use and strategies to address this. A Substance Use Stigma Framework was developed to guide analysis. RESULTS: Drug checking is operating in a context of structural stigma produced by criminalization. People fear criminal repercussions, anticipate stigma when accessing services, and internalize stigma resulting in shame and avoidance of services. A perceived hierarchy of substance use creates stigma results in stigma between service users and avoidance of sites associated with certain drugs. Participants frequently recommended drug checking to be located in more public spaces that still maintain privacy. CONCLUSIONS: Criminalization and societal views on substance use can deter service use. Strategies to mitigate stigma include employment of people with lived and living experience from diverse backgrounds; public yet private locations that preserve anonymity; and normalization of drug checking while decriminalization could address the root causes of stigma.

Vibrational sum frequency spectroscopy of thin film interfaces.

We describe a basic theoretical treatment of how film-substrate and substrate-environment (air, water, and solution) interfaces can be selectively probed by controlling the film thickness and beam angles in a visible-infrared sum frequency generation experiment. In this model, we also account for the unique interfacial environment that may have optical properties that differ from the adjacent bulk phases. We see that this affects components of the electric field that are perpendicular to the surface such as when p-polarized light is used. We then provide an example using the glass-polydimethylsiloxane-air system and model the fields at both surfaces of the polymer. This is followed by some practical considerations for setting up such experiments and some typical experimental results.

Exploring the use of infrared absorption spectroscopy and two-trace two-dimensional correlation analysis for the resolution of multi-component drug mixtures.

Community drug checking provides an essential service that responds to the unpredictable and variable supply of illicit drugs. Point of care detection of trace components using portable infrared spectrometers is a harm reduction measure to prevent overdose. This study investigates the ability of weighted subtraction and two-trace two-dimensional (2T2D) correlation analysis to reveal the presence of heroin in an opioid mixture that contains heroin and fentanyl mixed with caffeine as a cutting agent. In both methods, a spectral trace was identified that provided reasonably high correlation scores to heroin when compared to entries in drug libraries. The two-trace correlation analysis produced a higher match score, suggesting that future improvements in spectral unmixing methods may enhance the reliability of detecting trace components in drugs.

Ion Depletion in the Interfacial Microenvironment from Cell-Surface Interactions.

The nanoscale region immediately adjacent to surfaces, although challenging to probe, is directly responsible for local chemical and physical interactions between a material and its surroundings. Cell-surface contacts are mediated by a combination of electrostatic and acid-base interactions that alter the local environment over time. In this study, a label-free vibrational probe with a nanometer length scale reveals that the electrostatic potential at a silica surface gradually increases in the presence of bacteria in solution. We illustrate that the cells themselves are not responsible for this effect. Rather, they alter the interfacial chemical environment in a manner that is consistent with a reduction of the ionic strength to a level that is roughly four times lower than that of the bulk aqueous phase.

Variability in the unregulated opioid market in the context of extreme rates of overdose.

BACKGROUND: Drug checking uses analytical chemistry technologies to report on the composition of drugs from the unregulated market to reduce substance use-related risks, while additionally allowing for monitoring and reporting of the supply. In the context of an overdose crisis linked to fentanyl, we used drug checking data to examine variability within the illicit opioid supply. METHODS: In this time-series analysis, data was collected from a drug checking service in Victoria, Canada from November 2020 to July 2021. Drugs reported as opioids by participants of the service (N = 454) were analyzed to determine sample composition and paper spray mass spectroscopy was used to quantify low-concentration actives. Interquartile and statistical process control (SPC) analysis, namely standard deviation control charts, were used to examine the degree of variability among samples. RESULTS: Fentanyl was found in 96% of samples reported to be opioids, with a median concentration of 9%. Concentrations varied significantly, with a standard deviation of 7% for fentanyl and where nearly 20% of data points fell outside the control limits. Over half of the samples contained an additional and unexpected active, most commonly etizolam (43% of samples). Etizolam also showed a large level of variability, uncorrelated to that of fentanyl. CONCLUSIONS: Based on our chemical quantification and SPC analysis, a high degree of variability was found in opioid samples from the unregulated market in both the drugs detected and the concentrations of those drugs. This demonstrated the opioid crisis to be less attributable to a bad batch of drugs but rather the general variability found in the unregulated market.

Temperature-Dependent Infrared Refractive Index of Polymers from a Calibrated Attenuated Total Reflection Infrared Measurement.

We demonstrate a straightforward method by which a commonly available reference sample such as water can be used to calibrate an attenuated total internal reflection infrared absorbance measurement in order to account for the polarization of the beam incident on the internal reflecting element, and the spread of angles about the nominal angle of incidence. This enables quantitative comparison of attenuated total reflection-derived absorbance data with spectra calculated from optical constants. We then apply this calibration to the measurement of temperature-dependent absorption spectra of a polydimethylsiloxane sample. We illustrate that the extracted optical constants scale with the temperature-dependent changes in the polymer density better than the raw absorbance values on vibrational resonance.