Applying machine learning to international drug monitoring: classifying cannabis resin collected in Europe using cannabinoid concentrations.

In Europe, concentrations of ∆9-tetrahydrocannabinol (THC) in cannabis resin (also known as hash) have risen markedly in the past decade, potentially increasing risks of mental health disorders. Current approaches to international drug monitoring cannot distinguish between different types of cannabis resin which may have contrasting health effects due to THC and cannabidiol (CBD) content. Here, we compared concentrations of THC and CBD in different types of cannabis resin collected in Europe (either Moroccan-type, or Dutch-type). We then tested the ability of machine learning algorithms to classify the type of cannabis resin (either Moroccan-type, or Dutch-type) using routinely collected monitoring data on THC and CBD. Finally, we applied the optimal algorithm to new samples collected in countries where the type of cannabis resin was unknown, the UK and Denmark. Results showed that overall, Dutch-type samples had higher THC (Hedges' g = 2.39) and lower CBD (Hedges' g = 0.81) than Moroccan-type samples. A Support Vector Machine algorithm achieved classification accuracy exceeding 95%, with little variation in this estimate, good interpretability, and plausibility. It made contrasting predictions about the type of cannabis resin collected in the UK (94% Moroccan-type; 6% Dutch-type) and Denmark (36% Moroccan-type; 64% Dutch-type). In conclusion, we provide proof-of-concept evidence for the potential of machine learning to inform international drug monitoring. Our findings should not be interpreted as objective confirmatory evidence but suggest that Dutch-type cannabis resin has higher THC concentrations than Moroccan-type cannabis resin, which may contribute to variation in drug markets and health outcomes for people who use cannabis in Europe.

New psychoactive substances: challenges for drug surveillance, control, and public health responses.

The rapid emergence since the mid-2000s of a large and diverse range of substances originally designed as legal alternatives to more established illicit drugs (pragmatically clustered and termed new psychoactive substances; [NPS]) has challenged traditional approaches to drug monitoring, surveillance, control, and public health responses. In this section of the Series, we describe the emergence of NPS and consider opportunities for strengthening the detection, identification, and responses to future substances of concern. First, we explore the definitional complexity of the term NPS. Second, we describe the origins and drivers surrounding NPS, including motivations for use. Third, we summarise evidence on NPS availability, use, and associated harms. Finally, we use NPS as a case example to explore challenges and opportunities for future drug monitoring, surveillance, control, and public health responses. We posit that the current means of responding to emerging substances might no longer be fit for purpose in a world in which different substances can be rapidly introduced, and where people who use drugs can change preferences on the basis of market availability.

Responding to New Psychoactive Substances in the European Union: Early Warning, Risk Assessment, and Control Measures.

New psychoactive substances (NPS) are drugs that are not controlled by the United Nations international drug control conventions of 1961 and 1971 but that may pose similar threats to public health. Many of them are traded as "legal" replacements to controlled drugs such as cannabis, heroin, benzodiazepines, cocaine, amphetamines, and 3,4-methylenedioxymethamphetamine (MDMA). Driven by globalization, there has been a large increase in the availability and, subsequently, harms caused by these substances over the last decade in Europe. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is monitoring more than 670 NPS that have appeared on Europe's drug market in the last 20 years, of which almost 90% have appeared in the last decade. While some recent policy responses have been successful in reducing availability and sales of these substances in some settings - such as "legal highs" and "research chemicals" sold openly in the high street and online - and there are signs that growth in the market is slowing, new challenges have emerged. This includes monitoring a growing number of highly potent substances - including 179 synthetic cannabinoid receptor agonists and 28 fentanils - that can pose a high risk of life-threatening poisoning to users and can cause explosive outbreaks. This chapter briefly traces the origins of NPS, provides an overview of the situation in Europe, and discusses the work of the EMCDDA as part of a legal framework of early warning, risk assessment, and control measures that allows the European Union to rapidly detect, assess, and respond to public health and social threats caused by these substances.

Computer-aided (in silico) approaches in the mode-of-action analysis and safety assessment of ostarine and 4-methylamphetamine.

OBJECTIVE: This study exemplifies computer-aided (in silico) approaches in assessing the risks of new psychoactive substances emerging in the European Union. In this work, we (i) consider the potential of Ostarine exhibiting psychoactivity and (ii) anticipate potential activities and toxicities of 4-methylamphetamine. METHOD: The approach, termed in silico target prediction, suggests potential protein targets modulated by compounds given their chemical structure. This is achieved by first establishing the associations between chemical structure and protein targets using data from the bioactivity database, ChEMBL, via the use of two different computational algorithms. On the basis of the associations, protein targets and consequently the mode of action of novel compounds were predicted. RESULTS: For Ostarine, none of the targets anticipated are currently known to elicit psychoactivity. Furthermore, Ostarine is unlikely to cross the blood-brain barrier to reach relevant target sites on the basis of its physicochemical properties. For 4-methylamphetamine, toxicities were anticipated, that is, serotonin syndrome (based on the prediction of SERT) and other effects similar to related substances, that is, methamphetamine. CONCLUSION: From the two case studies, we showed that in silico target prediction appears to have potential in assessing new psychoactive compounds where experimental data are scarce. The applicability domain of target predictions when applied to psychoactive compounds needs to be established in future work.

Misuse of medicines in the European Union: a systematic review of the literature.

BACKGROUND: Although awareness of the misuse of medicines is increasing, data on the extent of the problem in the European Union (EU) are lacking. METHODS: In order to assess the magnitude and severity of the problem, a systematic review of the literature on the misuse of analgesics, opioid substitution medicines and sedatives/hypnotics (with the exception of benzodiazepines) was conducted using the PubMed and Web of Science databases. Relevant literature was identified between 2001 and 2011. RESULTS: The main groups of misused medicines include opioid analgesics, methadone, buprenorphine and Z-drugs. Regional trends in medicine misuse indicate heterogeneity across the EU with respect to misused medicine types and research activities. Prevalence, high-risk populations and factors contributing to medicine misuse are discussed. CONCLUSION: The implications of these findings for prevention, treatment, and policy in the EU are considered.

DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles.

Etonitazene and related 2-benzylbenzimidazoles are potent analgetics invented in the research laboratories of the Swiss pharmaceutical giant CIBA in the late 1950s. Though the unprecedented structure distinguishes this class of compounds from poppy-derived and other synthetic analgetics, a range of studies indicate that these drugs are selective µ opioid receptor agonists possessing morphine-like pharmacotoxicological properties in animals as well as humans. Several unscheduled members of this synthetically readily accessible class of opioids that are not controlled under the international and national drug control systems have recently emerged on the illicit drug market. Among them, isotonitazene has been implicated in at least 200 fatalities in Europe and North America. None of the 2-benzylbenzimidazole derivatives have been developed into medicines, but etonitazene and some of its derivatives have been used as receptor probes and in addiction behavior studies in animals. The unique structure has inspired research on such benzimidazoles and related benzimidazolones of which "brorphine" made its debut as one of the newest psychoactive substance to emerge on the illicit opioid drug market in mid-2019. This in-depth review provides a historical introduction, an overview on the chemistry, pharmacological profiles, adverse effects, addiction liability, regulatory status, and the impact on chemical neuroscience of the 2-benzylbenzimidazoles. Structurally related benzimidazoles with opioid and/or analgesic properties are also discussed briefly.

Legal highs on the Internet.

This article describes the findings of a descriptive analysis of 27 online drug retailers selling legal alternatives to illegal drugs, commonly referred to as "herbal highs" and "legal highs" in 2008 . The study attempted to quantify the online availability of drug retailers, to describe common products and characteristics in EU-based retail sales. The findings highlight the concern about the lack of objective information about products offered, including potential risks to health. Systems should be developed to assess the contents of products and the accuracy of information provided on the Internet, alongside continued monitoring of this market for "legal high" substances.

Will the Current COVID-19 Pandemic Impact on Long-term Cannabis Buying Practices?

: The COVID-19 pandemic and the response to have resulted in an increase in sales activity levels on darknet markets during the first 3 months of 2020, mainly related to cannabis products. One key question is whether more people will become used to this form of purchasing their drugs and will they continue with it post COVID-19 lockdown. As one-to-one encrypted communication services or social media apps are increasingly being used, monitoring and interdiction will become much more challenging.

Increasing potency and price of cannabis in Europe, 2006-16.

AIMS: To quantify changes in (i) potency (concentration of Δ9 -tetrahydrocannabinol; %THC), (ii) price (euros/g of cannabis) and (iii) value (mg THC/euro) of cannabis resin and herbal cannabis in Europe. DESIGN: Repeated cross-sectional study. SETTING AND PARTICIPANTS: Data collected from 28 European Union (EU) member states, Norway and Turkey by the European Monitoring Centre for Drugs and Drug Addiction. MEASUREMENTS: Outcome variables were potency, price and value for cannabis resin and herbal cannabis in Europe, 2006-16. Inflation was estimated using the Harmonised Indices of Consumer Prices. Mixed-effects linear regression models were used to estimate linear and quadratic time trends, with a random intercept and slope fitted to account for variation across countries. FINDINGS: Resin potency increased from a mean [95% confidence interval (CI)] of 8.14% THC (6.89, 9.49) in 2006 to 17.22 (15.23, 19.25) in 2016. Resin price increased from 8.21 euros/g (7.54, 8.97) to 12.27 (10.62, 14.16). Resin increased in value, from 11.00 mg THC per euro (8.60, 13.62) to 16.39 (13.68, 19.05). Quadratic time trends for resin potency and value indicated minimal change from 2006 to 2011, followed by marked increases from 2011 to 2016. Herbal cannabis potency increased from 5.00% THC (3.91, 6.23) to 10.22 (9.01, 11.47). Herbal price increased from 7.36 euros/g (6.22, 8.53) to 12.22 (10.59, 14.03). The value of herbal cannabis did not change from 12.65 mg of THC per euro (10.18, 15.34) to 12.72 (10.73, 14.73). All price trends persisted after adjusting for inflation. CONCLUSIONS: European cannabis resin and herbal cannabis increased in potency and price from 2006 to 2016. Cannabis resin (but not herbal cannabis) increased in the quantity of Δ9 -tetrahydrocannabinol per euro spent. Marked increases in resin potency and value from 2011 to 2016 are consistent with the emergence of new resin production techniques in European and neighbouring drug markets.

Assessing the toxicological significance of new psychoactive substances in fatalities.

The number of new psychoactive substances (NPS) has increased significantly, especially within the last 5 years. The EMCDDA conducts risks assessments of such substances, especially in relation to serious adverse events. Examination of the individual health risks of a substance is a fundamental requirement of the process. Based on a number of considerations, the Toxicological Significance Score has been developed to support the risk assessment of NPS by allowing the role of a substance in deaths to be better assessed and classified.

Drug affordability-potential tool for comparing illicit drug markets.

BACKGROUND: The importance of illicit drug price data and making appropriate adjustments for purity has been repeatedly highlighted for understanding illicit drug markets. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has been collecting retail price data for a number of drug types alongside drug-specific purity information for over 15 years. While these data are useful for a number of monitoring and analytical purposes, they are not without their limitations and there are circumstances where additional adjustment needs to be considered. This paper reviews some conceptual issues and measurement challenges relevant to the interpretation of price data. It also highlights the issues with between-country comparisons of drug prices and introduces the concept of affordability of drugs, going beyond purity-adjustment to account for varying national economies. METHODS: Based on a 2015 European data set of price and purity data across the heroin and cocaine retail markets, the paper demonstrates a new model for drug market comparative analysis; calculation of drug affordability is achieved by applying to purity-adjusted prices 2015 Price Level Indices (PLI, Eurostat). RESULTS: Available data allowed retail heroin and cocaine market comparison for 27 European countries. The lowest and highest unadjusted prices per gram were observed for heroin: in Estonia, Belgium, Greece and Bulgaria (lowest) and Finland, Ireland, Sweden and Latvia (highest); for cocaine: the Netherlands, Belgium and the United Kingdom (lowest) and Turkey, Finland, Estonia and Romania (highest). The affordability per gram of heroin and cocaine when taking into account adjustment for both purity and economy demonstrates different patterns. CONCLUSION: It is argued that purity-adjusted price alone provides an incomplete comparison of retail price across countries. The proposed new method takes account of the differing economic conditions within European countries, thus providing a more sophisticated tool for cross-national comparisons of retail drug markets in Europe. Future work will need to examine other potential uses of the drug affordability tool. LIMITATIONS: The limitations of this measure reflect primarily the limitations of the constituent data; in addition to issues inherent in collecting accurate data on illicit markets, analysis that relies on data collected from multiple countries is susceptible to discrepancies in data collection practices from country to country.

Drug supply indicators: Pitfalls and possibilities for improvements to assist comparative analysis.

Interventions to tackle the supply of drugs are seen as standard components of illicit drug policies. Therefore drug market-related administrative data, such as seizures, price, purity and drug-related offending, are used in most countries for policy monitoring and assessment of the drug situation. International agencies, such as the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and the UN Office of Drugs and Crime, also monitor and report on the drug situation cross-nationally and therefore seek to collect and make available key data in a uniform manner from the countries they cover. However, these data are not primarily collected for this purpose, which makes interpretation and comparative analysis difficult. Examples of limitations of these data sources include: the extent to which they reflect operational priorities rather than market changes; question marks over the robustness of and consistency in data collection methods, and issues around the timeliness of data availability. Such problems are compounded by cultural, social and contextual differences between countries. Making sense of such data is therefore challenging and extreme care needs to be taken using it. Nevertheless, these data provide an important window on a hidden area, so improving the quality of the data collected and expanding its scope should be a priority for those seeking to understand or monitor drug markets and supply reduction. In addition to highlighting some of the potential pitfalls in using supply indicators for comparative analysis, this paper presents a selection of options for improvements based on the current EMCDDA programme of work to improve their supply-related monitoring and analysis. The conceptual framework developed to steer this work may have wider application. Adopting this approach has the potential to provide a richer picture of drug markets, at both national and international levels, and make it easier to compare data between countries.

The drug situation in Europe: an overview of data available on illicit drugs and new psychoactive substances from European monitoring in 2015.

AIM: A central task for the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is to produce an annual report of the latest data available on drug demand and drug supply in Europe. This paper is intended to facilitate a better understanding of, and easier access to, the main quantitative European level data sets available in 2015. METHODS: The European reporting system formally covers all 28 European Union (EU) Member States, Norway and Turkey and incorporates multiple indicators alongside an early warning system (EWS) on uncontrolled new psychoactive substances (NPS). While epidemiological information is based largely on registries, surveys and other routine data reported annually, the EWS collects case-based data on an ongoing basis. The 2015 reporting exercise is centred primarily on a set of standardized reporting tools. RESULTS: The most recent data provided by European countries are presented, including data on drug use, drug-related morbidity and mortality, treatment demand, drug markets and new psychoactive substances, with data tables provided and methodological information. A number of key results are highlighted for illustrative purposes. Drug prevalence estimates from national surveys since 2012 (last year prevalence of use among the 15-34 age band) range from 0.4% in Turkey to 22.1% in France for cannabis, from 0.2% in Greece and Romania to 4.2% in the United Kingdom for cocaine, from 0.1% in Italy and Turkey to 3% in the Czech Republic and the United Kingdom for ecstasy, and from 0.1% or less in Romania, Italy and Portugal to 2.5% in Estonia for amphetamine. Declining trends in new HIV detections among people who inject drugs are illustrated, in addition to presentation of a breakdown of NPS reported to the EU early warning system, which have risen exponentially from fewer than 20 a year between 2005 and 2008, to 101 reported in 2014. CONCLUSIONS: Structured information is now available on patterns and trends in drug consumption in Europe, which permits triangulation of data from different sources and consideration of methodological limitations. Opioid drugs continue to place a burden on the drug treatment system, although both new heroin entrants and injecting show declines. More than 450 new psychoactive substances are now monitored by the European early warning system with 31 new synthetic cathinones and 30 new synthetic cannabinoid receptor agonists notified in 2014.

Prevalence of use and acute toxicity associated with the use of NBOMe drugs.

INTRODUCTION: The 25X-NBOMe series are N-2-methoxybenzyl analogues of the respective 2C-X substituted phenethylamine and include 25B-N(BOMe)2, 25B-NBOMe, 25C-NBOMe, 25D-NBOMe, 25E-NBOMe, 25G-NBOMe, 25H-NBOMe, 25I-NBOMe, 25N-NBOMe and 25iP-NBOMe. There are reports of their use as novel psychoactive substances and associated acute toxicity from Europe, the United States and elsewhere over the last five years. This review will discuss the epidemiology of use and pattern of acute toxicity associated with use of these compounds. METHODS: A PubMed search was performed using the search terms 'NBOMe', '25B-N(BOMe)2', '25B-NBOMe', '25C-NBOMe', '25D-NBOMe', '25E-NBOMe', '25G-NBOMe', '25H-NBOMe', '25I-NBOMe', '25N-NBOMe' and '25iP-NBOMe' covering the years 1966-2014. In addition, abstracts from the 2010-2014 congresses of the European Association of Poisons Centres and Clinical Toxicologists and the 2010-2013 North American Congress of Clinical Toxicology were reviewed using these search terms. Further information was obtained from the European Information System and Database on New Drugs co-ordinated by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). PREVALENCE OF USE: There are no national or international surveys collecting data on the prevalence of use of NBOMe drugs. The only information on prevalence of use is from two sub-population surveys of individuals who frequent nightclubs. Of 22,289 respondents of the 2013 Global Drugs Survey, 582 (2.6%) had previously used an NBOMe; the most commonly used NBOMe was 25I-NBOMe (442 respondents, 2.0% of whole cohort and 75.9% of those who had used an NBOMe). In a survey of 397 clubbers in London nightclubs in 2013, 11.8% had heard of the NBOMe drugs (compared with 96.0% for mephedrone), and 4.8% had ever used an NBOMe (compared with 76.6% for mephedrone). ACUTE TOXICITY: There were 29 published cases in the literature of acute toxicity associated with the use of an NBOMe: 25I-NBOMe - 23 cases; 25B-NBOMe - 3 cases; 25C-NBOMe - 3 cases. Commonly reported features include tachycardia (96.6%), hypertension (62.0%), agitation/aggression (48.2%), seizures (37.9%) and hyperthermia (27.6%). Five patients were reported to have developed acute kidney injury. There were an additional 25 reports of acute toxicity related to the use of 25I-NBOMe reported to the EMCDDA. The pattern of toxicity in these cases is similar to that seen in the published cases. NBOMe-related deaths. 25I-NBOMe has been detected in eight fatalities; in one of these, 25C-NBOMe was also detected. The role of the NBOMe drugs in these deaths has not been determined in all cases. CONCLUSIONS: Currently, there is evidence suggesting limited use of the NBOMe class of drugs as novel psychoactive substances compared with that of classical recreational drugs and other novel psychoactive substances such as mephedrone.

Acute recreational drug and new psychoactive substance toxicity in Europe: 12 months data collection from the European Drug Emergencies Network (Euro-DEN).

CONTEXT: Despite the potential for recreational drugs and new psychoactive substances (NPSs) to cause significant morbidity and mortality, there is limited collection of systematic data on acute drug/NPS toxicity in Europe. OBJECTIVE: To report data on acute drug/NPS toxicity collected by a network of sentinel centres across Europe with a specialist clinical and research interest in the acute toxicity of recreational drugs and NPS to address this knowledge gap. METHODS: Sixteen sentinel centres in 10 European countries (Denmark, Estonia, France, Germany, Ireland, Norway, Poland, Spain, Switzerland and the UK) collected data on all acute drug toxicity presentations to their Emergency Rooms (ERs) for 12 months (October 2013-September 2014); information on the drug(s) involved in the presentations was on the basis of patient self-reporting. RESULTS: Data were collected on a total of 5529 presentations involving 8709 drugs (median (interquartile range [IQR]): 1 (1-2) drugs per presentation), a median of 0.3% of all ER attendances. Classical recreational drugs were most common (64.6%) followed by prescription drugs (26.5%) and NPS (5.6%). The 'top five' drugs recorded were heroin (1345 reports), cocaine (957), cannabis (904), GHB/GBL (711) and amphetamine (593). 69.5% of individuals went to hospital by ambulance (peak time between 19:00 and 02:00 at weekends); the median (IQR) age was 31 (24-39) years and 75.4% were male. Although serious clinical features were not seen in most presentations and 56.9% were medically discharged from the ER (median length of stay: 4.6 hours), a significant number (26.5%) was agitated, in 10.5% the GCS was 8 or less and 35 presented in cardiac arrest. There were 27 fatalities with opioids implicated in 13. CONCLUSION: The Euro-DEN dataset provides a unique insight into the drugs involved in and clinical pattern of toxicity/outcome of acute recreational drug toxicity presentations to hospitals around Europe. This is complimentary to other indicators of drug-related harm and helps to build a fuller picture of the public health implications of drug use in Europe.

Presentations to the Emergency Department Following Cannabis use--a Multi-Centre Case Series from Ten European Countries.

Cannabis is the most commonly used illicit drug in Europe, and is generally regarded as having low acute toxicity. We present the findings of the first 6 months of data collection from the Euro-DEN project on presentations related to cannabis use to further understand the acute toxicity related to the use of cannabis. Data was extracted on clinical features, treatment and outcome from the Euro-DEN minimum dataset for all cases of acute recreational drug toxicity reported 1st October 2013 to 31st March 2014 for all cannabis-related presentations. Of 2198 presentations reported by 14 of the 16 Euro-DEN centres, 356 (16.2 %) involved cannabis either alone or together with other drugs/alcohol. There were 36 that involved lone use of cannabis (1.6 % of all presentations). Of the 35 non-fatal lone cannabis presentations, the most commonly reported features were neuro-behavioural (agitation/aggression 8 (22.9 %), psychosis 7 (20.0 %), anxiety 7 (20.0 %)) and vomiting 6 (17.1 %). Most patients (25, 71.4 %) received no treatment and 30 (85.7 %) were discharged/self-discharged from the ED. There was one fatality amongst these lone-cannabis cases: an 18-year-old male collapsed with an asystolic cardiac arrest whilst smoking cannabis and suffered hypoxic brain injury related to prolonged cardiac arrest. THC was detected in a urine sample taken at ED arrival; no other drugs were detected. Lone acute cannabis toxicity was typically associated with neuro-behavioural symptoms and vomiting. Although uncommon, severe toxicity including cardiovascular toxicity and death may be under-recognised, and it is important that Emergency Physicians are aware of this.