Abstract
Synthetic cannabinoids (SCs) are drugs of abuse that have become increasingly popular in both prison and homeless populations in the UK. This group of novel psychoactive substances (NPS) have had devastating health effects on users whilst also compromising the safety of other prisoners and staff in the prison environment. In order to tackle drug-associated harm in the European Union (EU), the Council of the European Union devised the EU drugs strategy 2021-2025. This thesis follows two focus areas set out in this strategy; Research, Innovation, and Foresight, and Drug Supply Reduction.A lack of available data on the interaction of SCs with human receptors means that their mechanism of action in the body is poorly understood. Although often named synthetic cannabinoid receptor agonists due to their potent agonism of cannabinoid receptors 1 and 2, little is known regarding SC interactions with other enzymes. Many severe side effects associated with SCs cannot be tracked with their cannabinoid receptor agonism. With previous literature suggesting that the SC, WIN,55,212-2, inhibits monoamine oxidase A (MAO-A), a study was undertaken to demonstrate that SCs were in fact MAO-A selective inhibitors over MAO-B, potentially increasing the levels of tyramine in the body which could account for certain associated side effects. A combination of in silico and experimental kinetic studies were carried out, identifying the linked group as a structural SC component that affects the affinity of the SC to monoamine oxidase enzymes.
Analysing the structural components of SCs is therefore important for greater understanding of SC impacts to users. Additionally, foresight into the future of the rapidly developing SC drug market can be gained through researching patterns in the SC market over the past 15 years. A study investigating the structural evolution of SCs has been carried out, alongside key legislative milestones in the European Union and across the world. The study involves a full analysis of the 237 SCs monitored by the European Monitoring Centre of Drugs and Drug Addiction (EMCDDA) between December 2008 and July 2022, analysing separately their four structural features: core, tail, linker, and linked groups. Importantly, this study identifies a clear structural evolution in emerging SC compounds, following generic legislation introduced into China in 2021 to curb SC production. Following the introduction of this ruling, 21 out of 23 newly identified SCs on the EU market were sufficiently structurally evolved that they evaded the new legislation. This indicates that the introduction of legal responses can have unintended consequences, driving the production of structurally evolved SCs. Additionally, with similar patterns identified following other legislative milestones, SC structural evolution can be anticipated alongside the introduction of future regulations.
The second half of this thesis investigates drug supply reduction through innovation. SC detection is particularly challenging for law enforcement and forensic scientists in illicit drug analysis. Clandestine chemists have developed new compounds to increase potency and evade legislative controls across the world. Additionally, seized drug samples can be found on a range of matrices, biological or physical, and often contain other illicit compounds and adulterants. Consequently, portable NPS detection methods are an ever-increasing field of research with the aim of decreasing the time it takes to return drug analysis results. This is crucial for clinical settings, for example when rapidly treating overdose patients, and for prison personnel, when testing items going into a prison. An extensive critical review of the literature investigates current portable detection technologies, identifying benefits and disadvantages of each method, with scope for improvement.
Fluorescence spectral fingerprinting (FSF) is a technique shown to rapidly detect a range of SC compounds in methanol and in spiked saliva with minimal sample processing. However, to ensure this technology can be utilised effectively, it is important to enhance the sensitivity and discriminatory abilities. To achieve this, a model set of compounds were synthesised that were structurally analogous to seized SC compounds. Using these, alongside SC standards, a study was carried out to show the potential of FSF in discriminating structurally similar compounds. Additionally, density-functional theory (DFT) and time-dependent DFT was used to understand the photochemical degradation of these compounds. Crucially, by employing photochemical degradation via ultraviolet (UV) irradiation, FSF was shown to detect a new family of SC compounds, OXIZIDs, that were previously undetectable with this method prior to degradation.
With the confirmation that fluorescence-based detection was a valuable technique for the analysis of a diverse range of SC compounds, a second study was employed, developing a portable, handheld device. This device has been designed to detect SCs directly on a range of physical matrices, including paper, fabric, and herbal material, without extraction. This method involved the interpretation of emission spectra, manipulating specific spectral features for analyte detection. Authentic seized drug samples have been analysed using a range of laboratory techniques and then used to confirm the devices’ utility for in-field detection. Importantly, the device has been used to detect a second group of NPS, benzodiazepines, which is fast becoming a serious drug of concern, especially in Scottish prisons, with high associated mortality rates.
| Date of Award | 15 Nov 2023 |
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| Original language | English |
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| Supervisor | Christopher Pudney (Supervisor) & Simon Lewis (Supervisor) |