Incidence and characteristics of the nocebo response from meta-analyses of the placebo arms of clinical trials of olanzapine for bipolar disorder.

OBJECTIVES: In the clinical setting, the nocebo phenomenon is where clinical worsening or adverse events occur as a response to a treatment, in a situation in which conditioning from previous treatment exposure and/or expectations of sickness or symptoms lead to sickness and symptoms in a conditioned or expectant individual. The nocebo response may thus be a confounder in clinical treatment and clinical research. There is a need to know how to predict if an individual is likely to be a nocebo responder, and how significant and commonplace the nocebo effect might be. METHODS: An analysis was conducted on nine placebo-controlled, randomized clinical trials of olanzapine for the treatment of bipolar disorder using data from placebo-treated study participants only. Data were analysed to identify participant or study characteristics associated with a nocebo event, defined as any treatment-emergent adverse event (TEAE) or an increase in score from baseline to endpoint for primary measures of clinical symptoms. RESULTS: A total of 1185 participants were randomized to placebo, of whom 806 (68%) reported a TEAE. Hamilton Depression Rating Scale (HDRS) data were only available for 649 placebo-treated participants, of whom 321 (49.5%) demonstrated worsening. Nocebo events were significantly associated with: not being treatment-naïve, younger age, being located in the USA, being a participant in an earlier study, and being classified as obese compared with normal weight. CONCLUSIONS: A pattern to identify nocebo responders did not emerge, although some prognostic variables were associated with a greater probability of nocebo response. There was some evidence to support the role of expectancy as a cause of nocebo reactions.

Comparing two seized drug workflows for the analysis of synthetic cannabinoids, cathinones, and opioids.

As the challenges faced by drug chemists persist, due to the presence of emerging drugs, laboratories continue to look for new solutions, ranging from existing methods to implementation of entirely new technology. A common barrier for making workflow changes is a lack of pre-existing data demonstrating the potential impact of these changes. In this study, we compare, qualitatively and quantitatively, an existing workflow for seized drug analysis to an experimental workflow. Four chemists were asked to analyze a total of 50 mock case samples across the two workflows. The existing workflow employed color tests for screening alongside general purpose GC-FID and GC-MS analyses for confirmation. The experimental workflow combined DART-MS screening with class-specific (targeted) GC-MS analysis for confirmation. Comparison of the workflows showed that screening by DART-MS required the same amount of time as color tests but yielded more accurate and specific information. Confirmation using the existing workflow required more than twice the amount of instrument time and data interpretation time while also presenting other analytical challenges that prevented compound confirmation in select samples. Targeted GC-MS methods simplified data interpretation, reduced consumption of reference materials, and addressed almost all limitations of general-purpose methods. While the experimental workflow requires modifications and answering of additional research questions, this study shows how rethinking analytical workflows for seized drug analysis could reduce turnaround times, backlogs, and standards consumption. It also demonstrates the potential impact of being able to investigate workflow changes prior to implementation.

A framework for the development of targeted gas chromatography mass spectrometry (GC-MS) methods: Synthetic cannabinoids.

With the increased presence of novel psychoactive substances (NPSs) in casework, drug analysis has become more challenging. To address these challenges, new screening technologies with improved specificity are being implemented, allowing for the creation and adoption of targeted confirmatory analyses that produce more conclusive results. This paper outlines a six-step, data-driven, framework to develop and evaluate gas chromatography mass spectrometry (GC-MS) methods for targeted classes of drugs. The process emphasizes maximizing retention time differences (to minimize the potential for retention time acceptance windows to overlap) and understanding the trade-offs between sensitivity and reproducibility using a test solution containing pairs of compounds that are difficult to distinguish. The method is then evaluated by expanding the panel of compounds analyzed, identifying limitations in compound discrimination, comparing to current methods, and analyzing representative casework to establish usability. To demonstrate this framework, a method for synthetic cannabinoids was created. The developed method utilizes a DB-200 column and an isothermal temperature program. It was found that sensitivity could be adjusted, without compromising reproducibility, by altering the split ratio and injection volume. The targeted method successfully differentiated 50 cannabinoids based on either retention time differences or mass spectral dissimilarity - determined using a newly developed spectral comparison test. Compared to a general method used for casework, the targeted method was an order of magnitude more sensitive, a minute shorter, and provided major increases in retention time differences. This framework can be implemented and adapted to develop targeted methods for other applications or compound classes.

Development and evaluation of a synthetic cathinone targeted gas chromatography mass spectrometry (GC-MS) method.

To address challenges associated with the increased prevalence of novel psychoactive substances (NPSs), laboratories often adopt new techniques or new methods with the goal of obtaining more detailed chemical information with a higher level of confidence. To demonstrate how new methods applied to existing techniques can be a viable approach, a targeted gas chromatography mass spectrometry (GC-MS) method for synthetic cathinones was developed. To create the method, a range of GC-MS parameters were first investigated using a seven-component test solution with the goal of minimizing compounds with overlapping acceptance windows by maximizing retention time differences within a reasonable runtime. Once developed, the targeted method was evaluated through several studies and was compared to a general GC-MS confirmatory method. The method produced a twofold increase in retention time differences of the test solution compounds with a 3.83-min shorter runtime than the general method. Limitations of the method were also studied by analyzing an additional forty-eight cathinones to identify instances where definitive compound identification may not be possible due to overlapping acceptance windows and mass spectra. Thirty-eight pairs of compounds had retention times differences of less than 2% and, of those thirty-eight, one pair had indistinguishable mass spectra. A set of case samples were also analyzed using the method to evaluate suitability for casework. An increase in split ratio was required to obtain acceptable sensitivity. The development of this method is part of a larger project to measure benefits and drawbacks of different drug chemistry workflows.

Development and evaluation of a synthetic opioid targeted gas chromatography mass spectrometry (GC-MS) method.

As seized drug casework becomes increasingly complex due to the continued prevalence of emerging drugs, laboratories are often looking for new analytical approaches including developing methods for the analysis of specific compounds classes. Recent efforts have focused on the development of targeted gas chromatography mass spectrometry (GC-MS) confirmation methods to compliment the information-rich screening results produced by techniques like direct analysis in real time mass spectrometry (DART-MS). In this work, a method for the confirmation of synthetic opioids and related compounds was developed and evaluated. An 11-component test solution was used to develop a method that focused on minimizing overlapping retention time acceptance windows and understanding the influence of instrument parameters on reproducibility and sensitivity. Investigated settings included column type, flow rate, temperature program, inlet temperature, source temperature, and tune type. Using a DB-200 column, a 35-min temperature ramped method was created. It was evaluated against a suite of 222 synthetic opioids and related compounds, and successfully differentiated all but four compound pairs based on nonoverlapping retention time acceptance windows or objectively different mass spectra. Compared to a general confirmatory method used in casework, the targeted method was up to 25 times more sensitive and provided at least a two-fold increase in retention time differences. Analysis of extracts from actual case samples successfully demonstrated utility of the method and showed no instance of carryover, although the high polarity column required wider retention time windows than other columns.

An Easy to Implement Approach for Laboratories to Visualize Particle Spread During the Handling and Analysis of Drug Evidence.

Recent work has shown that detectable levels of drugs exists on nearly all surfaces within a forensic laboratory - especially within the drug chemistry unit. This is an expected occurrence due to the handling and opening of drug evidence that contains powder material. The process of opening evidence, which produces aerosolized particulate that can settle on surfaces throughout the lab, has never been visualized. This work presents the first attempt to visualize the spread of particulate throughout the laboratory during the analysis of drug evidence and introduces an easy to implement approach laboratories can use to evaluate their specific protocols. By creating two simulated bricks of drugs that contained fluorescent particles, the spread of particulate was able to be monitored throughout the evidence handling process up to and including cleaning of surfaces after analysis. The protocols in this work, showed the spread of particulate, prior to cleaning, to be quite extensive, with transfer onto surfaces and items that were handled. In this study, cleaning with methanol after processing the evidence was shown to be effective at removing nearly all particulate that was released in the process. The use of visualization techniques such as this demonstrate promise for helping laboratories identify processes in their own protocols that may contribute to drug background levels and educate forensic chemists how trace residues spread.

What's in the bag? Analysis of exterior drug packaging by TD-DART-MS to predict the contents.

The need for a safe and reliable presumptive test for law enforcement, first responders, and laboratory personnel is critical in the era of dangerous synthetic opioids and other novel psychoactive substances. Obtaining drug identification information without handling bulk powder is one way of accomplishing this task. This work evaluates whether trace residue on the exterior of drug packaging presents a potential source for presumptive testing. Utilizing a wipe-based approach, the outside of the packaging of nearly 200 case exhibits were sampled and analyzed by thermal desorption direct analysis in real time mass spectrometry (TD-DART-MS). While residue on the law enforcement (outer) packaging was a poor indicator of the contents (less than 50% accurate), the exterior of the drug (inner) packaging was shown to be an excellent indicator of its contents (92% accurate). Quantitative analysis of the wipes, using liquid chromatography mass spectrometry (LC-MS/MS) showed that typical masses of residue on the exterior of packaging ranged from single to tens of micrograms - enough for detection by a number of trace detection tools. These initial results demonstrate that wipe-based trace sampling approaches present a promising, reliable, and safe method for presumptive testing by law enforcement, first responders, or laboratory personnel.

A snapshot of drug background levels on surfaces in a forensic laboratory.

While background studies have been commonplace in many occupational fields for a long time, attempts to understand the chemical background in forensics labs has been largely understudied. Such studies can help define the efficiency of cleaning procedures and the integrity of collected data, which is becoming increasingly important due to improving sensitivity of instrumentation and the prevalence with which potent drugs of abuse, such as the opioids, are being seen. The results from this study provide a snapshot of the drug background levels on surfaces in a laboratory system comprised of a central laboratory and two satellite laboratories. Samples were collected from work surfaces by swiping with meta-aramid wipes, and extracted for analysis by LC/MS/MS, for quantitation, and TD-DART-MS, for non-targeted screening. Surfaces were sampled from within the drug unit (where drug evidence is processed) and the evidence receiving unit (where drug cases are handled) in all laboratories as well as the report writing area, the toxicology unit and the crime scene unit in the central laboratory. Results showed that the background was restricted primarily to the benches, balances, and instrumentation within the drug unit - with approximately an order of magnitude higher concentrations observed on the balances, compared to the benches. Higher levels were also observed in analyst specific surfaces when compared to general use surfaces within the drug unit - which corresponded to where bulk evidence handling was completed. Background in the evidence receiving and report writing sections was minimal. Comparison of the main laboratory to the satellite laboratories showed similarities amongst frequently encountered drugs like cocaine, but noticeable differences in opioids which could be attributed to differences in the make-up of exhibits each laboratory receives. Understanding the background levels of drugs in a forensic laboratory environment is crucial to improving cleaning protocols, helping define detection limits for highly sensitive analyses, and providing additional results to the broader community that has been establishing background levels in other environments.