Smartphone swabs as an emerging tool for toxicology testing: a proof-of-concept study in a nightclub.

OBJECTIVES: Smartphones have become everyday objects on which the accumulation of fingerprints is significant. In addition, a large proportion of the population regularly uses a smartphone, especially younger people. The objective of this study was to evaluate smartphones as a new matrix for toxico-epidemiology. METHODS: This study was conducted during two separate events (techno and trance) at an electronic music nightclub in Grenoble, France. Data on reported drug use and whether drugs were snorted directly from the surface of the smartphone were collected using an anonymous questionnaire completed voluntarily by drug users. Then, a dry swab was rubbed for 20 s on all sides of the smartphone. The extract was analyzed by liquid chromatography coupled to tandem mass spectrometry on a Xevo TQ-XS system (Waters). RESULTS: In total, 122 swabs from 122 drug users were collected. The three main drugs identified were MDMA (n=83), cocaine (n=59), and THC (n=51). Based on declarative data, sensitivity ranged from 73 to 97.2 % and specificity from 71.8 to 88.1 % for MDMA, cocaine, and THC. Other substances were identified such as cocaine adulterants, ketamine, amphetamine, LSD, methamphetamine, CBD, DMT, heroin, mescaline, and several NPS. Numerous medications were also identified, such as antidepressants, anxiolytics, hypnotics, and painkillers. Different use patterns were identified between the two events. CONCLUSIONS: This proof-of-concept study on 122 subjects shows that smartphone swab analysis could provide a useful and complementary tool for drug testing, especially for harm-reduction programs and toxico-epidemiolgy studies, with acceptable test performance, despite declarative data.

Cannabidiol (CBD): Confronting consumers' expectations of therapeutic benefits with pharmacological reality.

In recent years, the increase in cannabidiol (CBD) sales in Europe has raised questions regarding the legal status of this product, as well as its safety of use. Consumers seem to be looking for solutions to various health issues. However, the scientific reality is much more nuanced. The European CBD market emerged in Switzerland in 2016 and subsequently expanded across the continent. This expansion has been facilitated by the establishment of delta-9-tetrahydrocannabinol (THC) concentration limits for these products. However, the current market offers a diverse range of CBD products, often lacking clear information on raw materials, product concentrations and recommended dosages. Regulating these products is challenging, as the appropriate classification of CBD remains uncertain. CBD products are in high demand worldwide, with many people seeking alternative treatments for medical conditions or general health and well-being benefits. However, the use of CBD products often relies on self-medication and lacks sufficient scientific evidence. Improved communication between patients and healthcare professionals is needed to ensure informed decisions and address potential interactions with other medications. Scientific evidence on CBD is currently limited and the efficacy of CBD-containing products has only been proven in clinical trials for Epidyolex® as an add-on therapy. There is no consensus on the long-term safety, appropriate dosage, schedules or administration routes for CBD. Health claims associated with CBD are not consistent with the available scientific research, which is still in its early stages. Further clinical research is needed to establish the efficacy and safety of CBD in various medical conditions. The enthusiasm surrounding CBD-based products should be tempered by the limited scientific evidence of their efficacy, the inadequacy of patient expectations, regulatory concerns and potential drug interactions.

Patterns of ketamine use among people with substance use disorder in France: Multisource analysis of the data from the French Addictovigilance Network.

BACKGROUND: Due to its psychoactive effects, ketamine has become a drug used for non-medical purpose. OBJECTIVES: To assess the latest trends in ketamine use among people with substance use disorder and to characterize its clinical complications using complementary health data sources of the French Addictovigilance Network. METHODS: First, we extracted all reports involving ketamine from 2012 to 2021 from the database of the OPPIDUM program (i.e., a multicentric program conducted in collaboration with hundreds of substance abuse treatment facilities that collects data on drugs used by subjects with substance use disorders). We described the reports globally and the changes from 2012 to 2021. Second, we extracted all cases involving ketamine from July 2020 to December 2022 from the French National Pharmacovigilance Database (BNPV). We identified the cases related to ketamine use among people with substance use disorder and described them. RESULTS: There was a 2.5-fold increase in the number of ketamine users with substance use disorder in the OPPIDUM program, from 35 (0.7%) subjects in 2012 to 89 (1.7%) subjects in 2021. There was an increase in the proportion of subjects who were daily users, had distress upon discontinuation, and presented addiction. There were 238 cases related to ketamine use among people with substance use disorder in the French National Pharmacovigilance Database from July 2020 to December 2022. Among them, 94 (39.5%) cases involved ketamine use disorder, 20 (8.4%) cases involved urinary tract and kidney symptoms, and 13 (5.5%) cases involved hepatobiliary symptoms. CONCLUSION: The trend observed over 10 years reflects the growth in ketamine use among people with substance use disorder, although it does not allow to estimate the rates of non-medical use of ketamine in the general population. Ketamine-induced uropathy and cholangiopathy are reported in ketamine users with substance use disorder, especially in case of repeated and/or prolonged use of high doses.

Trends in Fatal Poisoning Among Drug Users in France From 2011 to 2021: An Analysis of the DRAMES Register.

Importance: The DRAMES (Décès en Relation avec l'Abus de Médicaments Et de Substances) register is a database of drug-related deaths with the aim of identifying the psychoactive substances associated with and estimating the trends in these deaths. Our novel approach is based on the collection of data on all deaths for which toxicology experts have performed analyses. Objective: To describe drug-related deaths in France and report trends over an 11-year period. Design, Setting, and Participants: This case series used a national register to assess 4460 drug-related deaths that occurred from 2011 to 2021 in France. Data analyses were performed from January 1, 2012, to December 31, 2022. Main Outcomes and Measures: Demographic characteristics; medical and substance abuse history; forensic autopsy findings; and toxicology reports. Results: Among the 4460 deceased individuals (mean [SD] age, 37.8 [10.5] years), the mortality rate was highest among men (sex ratio, 4.4:1). Of the deaths involving a single or predominant drug, the legal substitution product, methadone, was the leading cause of death during the entire study period, ahead of heroin-44.7% and 35.9% for methadone vs 15.8% and 21.8% for heroin in 2011 and 2021, respectively. Between 2011 and 2021, most of the drug-related deaths shifted from licit to illicit drugs, and statistically significant variations were found for buprenorphine, cocaine, heroin, methadone, and other licit opioids. Deaths related to polydrug use increased from 23.2% in 2011 to 30.6% in 2021. In this context, opioids remained associated with most deaths, with at least 1 opioid being involved in approximately 9 of 10 cases (85.9%) in 2021. However, the main trend was the dramatic increase in drug combinations with cocaine, from less than one-third of cases in 2011 (30.8%) to more than half in 2021 (57.8%). Conclusions and Relevance: This case series assessment of 4460 drug-related deaths found that opioids used alone or in combination were the main contributor to drug-related deaths, despite having a lower prevalence than other drugs. This finding is similar to that of other countries; however, in France licit methadone was the leading cause of opioid-related deaths (ahead of heroin) during the study period. Deaths associated with use of cannabis, new psychoactive substances, and stimulants (including amphetamine-type stimulants and cocaine, especially in combination) have increased and should be closely monitored.

NPAideS: a drug-checking study among 3-methylmethcathinone (3-MMC) users.

BACKGROUND: 3-methylmethcathinone (3-MMC) has been available on the European drug market for several years, but an increase in its availability seems to have occurred around 2020, associated with reports of harm and death. We aimed to analyze the composition of the supposed 3-MMC samples purchased and its concordance with the assumed composition of the drug. METHODS: A prospective multicenter (n = 6) study was conducted between February 2021 and September 2021 in Auvergne-Rhone-Alpes, France. The inclusion criteria were: 3-MMC users over 18 years of age in contact with a community-based organization (CBO) called AIDES. Consumption was evaluated with an anonymized questionnaire and samples of 3-MMC powder were analyzed with a combination of qualitative (GC-MS) and quantitative methods (UPLC-MS/MS), to compare the assumed and real compositions of the products purchased. RESULTS: We studied 45 samples provided by 33 users. The study population was predominantly male (91%), with a median age of 40 years, most were university graduates and regular users of 3-MMC. Intravenous drug use was reported by 15.2% of the population. Most of the users bought their 3-MMC online via the Clear Web. Drug testing was requested by 86% of the users, highlighting the need for this type of harm reduction strategy. The purity of the 3-MMC powder samples tested ranged from 21 to 98%. Other NPS drugs, such as 4-CEC (4-chloroethcathinone), 4-MMC, and 2-fluorodeschloroketamine (2-FDCK), supplied as methoxphenidine (MXP), were also detected. CONCLUSION: This prospective study shows that 3-MMC purity and dose vary considerably. It also describes the characteristics of 3-MMC users and their expectations of a drug-checking program. Our data suggest that drug-checking services may be useful in this population. Health associations and laboratories should work together to help increase access to such programs.

[Increase of overdose and deaths related to methadone during COVID-19 epidemic in 2020]. / Augmentation des surdoses et décès en lien avec la consommation de méthadone durant la crise sanitaire liée au COVID-19 en 2020.

INTRODUCTION: Due to the risk of overdoses increase especially with methadone, a reinforced monitoring has been set up by the French Addictovigilance Network following the first lockdown related to coronavirus disease 2019 (COVID-19). In this context, we managed a specific study to analyze overdoses related to methadone in 2020 compared to 2019. MATERIAL AND METHODS: We analyzed methadone-related overdoses which occurred in 2019 and 2020 from two sources: DRAMES program (deaths with toxicological analysis) and the French pharmacovigilance database (BNPV) (overdoses that did not lead to death). RESULTS: Data from DRAMES program in 2020 show methadone as the first drug involved in deaths as well as an increase in deaths: in number (n=230 versus n=178), in proportion (41% versus 35%) and number of deaths per 1000 exposed subjects (3.4 versus 2.8). According to BNPV, the number of overdose increased in 2020 compared to 2019 (98 versus 79; i.e., 1.2-fold increase) particularly during several target periods: first lockdown, end of lockdown/summer period and second lockdown. In 2020, a higher number of cases were observed in April (n=15) and May (n=15). Overdoses and deaths occurred in subjects enrolled in treatment programs or not (naïve subjects/occasional users who obtained methadone from street market or family/friends). Overdoses resulted from different factors: overconsumption, multiple drug use with depressants drugs or cocaine, injection, consumption for sedative, recreational purposes or voluntary drug poisoning. DISCUSSION/CONCLUSION: All these data show an increase of morbidity and mortality related to methadone during COVID-19 epidemic. This trend has been observed in other countries.

Non-medical use of baclofen: A case series and review of the literature.

BACKGROUND: Baclofen is widely used for spastic disorders and, most recently, for addictive disorders. The first signals of baclofen abuse occurred in the last decade. This study aims to assess the motives, diversion sources, and routes of administration associated with the non-medical use of baclofen and examine health problems related to the non-medical use of baclofen. METHODS: Spontaneous reports of baclofen abuse reported to the addictovigilance centre of East France were analysed. A literature search was conducted using PubMed®, Web of Sciences®, and Google Scholar® databases. Both investigations were performed in February 2021 without a time limit. RESULTS: Forty-six cases were analysed (33 from the literature review and 13 from the addictovigilance base). Baclofen's non-medical use mainly affected male subjects with addictive history, but issues of primary abuse in subjects without any substance abuse history were also observed. Euphoria search was the most common reason for misuse. The route of administration included oral, snorting, and sublingual use. Some cases involving illegal sources were also observed. Most patients misusing baclofen presented severe complications, mainly represented by neurological and respiratory disturbances. Physical and psychological dependence on baclofen was observed in three persons. CONCLUSIONS: Although baclofen abuse remains relatively infrequent or (most likely) underestimated, this study helped confirm baclofen's intrinsic abuse potential and make visible the baclofen-abuse-related health visible harms. Careful consideration and benefit-risk analysis should be employed when prescribing baclofen, and emergency departments should be aware of baclofen dangers in abuse situations.

The opioid epidemic: A worldwide exploratory study using the WHO pharmacovigilance database.

BACKGROUND AND AIMS: The current opioid epidemic in the United States began 20 years ago and has become the leading cause of accidental deaths in the country. This crisis prompted us to explore trends in opioid abuse and dependence worldwide. We sought to identify other countries at high-risk of opioid use disorders, using the World Health Organization's (WHO) pharmacovigilance database. METHODS: We performed a disproportionality analysis using VigiBase, the WHO Global Individual Case Safety Report (ICSR) database. Five opioids used worldwide were included: oxycodone, fentanyl, morphine, tramadol, and codeine. We extracted all ICSRs associated with the drugs of interest, considered as suspect medication and recorded up until 5 June 2021, using the narrow Standardised MedDRA Query (SMQ) for drug abuse and dependence. Countries with at least one ICSR for each of the five opioids were retained. The relationship between the use of a drug (i.e. an opioid) and the occurrence of an adverse drug reaction (i.e. drug abuse and dependence) for each country was assessed by calculating the information component (IC) and its 99.9% CI [IC0005 ; IC9995 ], using a quasi-Bayesian confidence propagation neural network (BCPNN). A hierarchical cluster analysis (Ward's method) of the IC0005 value for each of the five opioids was performed to identify subgroups of countries with similar reported risks of opioid abuse and dependence. RESULTS: Among 21 countries, the optimal number of clusters was calculated to be four, each with a Jaccard index >0.5 (0.95, 0.78, 0.65 and 0.75, respectively). Six countries with the highest signals of drug abuse and dependence were identified in cluster 1, with significant CIs for the five opioids of interest (IC0005 > 0), ranging from 0.9 to 5.8 for the lower endpoint. CONCLUSIONS: There appear to be four distinct clusters of countries with similar opioid abuse and dependence profiles. The group with the highest reported risk for the opioids oxycodone, fentanyl, morphine, tramadol and codeine includes Australia, Canada, France, Germans, the United Kingdom and the United States.

Association between NMDAR antagonists, drug abuse and dependence: A disproportionality analysis from the WHO pharmacovigilance database.

Ketamine and dextromethorphan are widely abused psychoactive substances. Inhibition of N-methyl-d-aspartate receptors (NMDARs) results in neurobehavioural effects including hallucinations, "out of body" sensations and dissociative effects. However, little is known about a possible extended addictive class effect linked to pharmacologically-related amino-adamantane derivatives (e.g., amantadine and memantine). Using a quasi-Bayesian analytic method, we investigated the potential association between the use of approved NMDAR antagonists (i.e., dextromethorphan, ketamine, amantadine and memantine) and the reporting of drug abuse and dependence in the WHO pharmacovigilance database (VigiBase®), which includes >21 million individual case safety reports collected from >130 countries. This disproportionality analysis identified a significant association for all investigated drugs: dextromethorphan (IC = 3.03 [2.97-3.09]), ketamine (IC = 1.70 [1.57-1.83]), amantadine (IC = 0.21 [0.06-0.35]) and memantine (IC = 0.27 [0.13-0.40]), suggesting a class effect for drug abuse and dependence. This first signal requires further investigations, but health professionals need to be alert to the potential of abuse of NMDAR antagonists, especially in the current "opioid epidemic" context, due to their growing interest as non-opioid antinociceptive drugs.

[Pharmacology of cannabidiol: Red flags, consequences and risks in humans]. / Pharmacologie du cannabidiol : points de vigilance, conséquences et risques chez l'homme.

Scientific knowledge about cannabidiol (CBD) demonstrates that CBD is a substance that is not pharmacologically inert. If it does not act efficiently on cannabinoid receptors (those where tetrahydrocannabidol [THC] is fixed), it acts on brain receptors, especially on dopamine and serotonin receptors, making it a psychoactive product in its own right. Its consumption can thus have psychoactive effects, such as sedation and drowsiness for example. In humans, interactions between CBD and drugs such as anti-epileptics, anticoagulants, immunosuppressants or methadone, have been highlighted. Therefore, the drug treatment of patients with chronic diseases may be impacted because of the unknown interaction with CBD. In addition, a recent experimental study has shown that the use of CBD by vaping (e-cigarette) generated by pyrolysis, products containing THC; it could result in possible negative health consequences for the user in terms of clinical effects and/or collateral effects (including on driving). Finally, therapeutic claims (outside of authorized drugs) that are purely speculative at this stage may divert users from proven management (stopping their drug treatment in favor of CBD or "self-medication"). All these data underline the importance of implementing measures related to the accessibility of CBD in order to avoid public health consequences and to better protect the users.

A meta-epidemiological study found lack of transparency and poor reporting of disproportionality analyses for signal detection in pharmacovigilance databases.

OBJECTIVES: To review and appraise methods and reporting characteristics of pharmacovigilance disproportionality analyses. STUDY DESIGN AND SETTING: We randomly selected 100 disproportionality analyses indexed in Medline found during a systematic literature search. We then extracted and synthetized methodological and reporting characteristics using seven key items: (1) title transparency; (2) protocol pre-registration; (3) date of data extraction and analysis; (4) outcome, population, exposure and comparator definitions; (5) adjustment and stratification of results; (6) method and threshold for signal detection; (7) secondary and sensitivity analyses. RESULTS: We found that methods used to generate disproportionality signals were extremely heterogeneous; there were nearly as many unique analyses as studies. The authors used various populations, methods, signal detection thresholds, adjustment or stratification variables, generally without justification for their choice or pre-specification in protocols. Moreover, 78% of studies failed to report methods for case, adverse drug reactions or comparator selection and 32 studies did not define the threshold for signal generation. CONCLUSION: Our survey raises major concerns regarding all aspects of disproportionality analyses that could lead to misleading results and generate unjustified alarms. We advocate for a strong and transparent rationale for variable selection, choice of population and comparators pre-specified in a protocol and assessed by sensitivity analyses.

Leveraging the Variability of Pharmacovigilance Disproportionality Analyses to Improve Signal Detection Performances.

Background: A plethora of methods and models of disproportionality analyses for safety surveillance have been developed to date without consensus nor a gold standard, leading to methodological heterogeneity and substantial variability in results. We hypothesized that this variability is inversely correlated to the robustness of a signal of disproportionate reporting (SDR) and could be used to improve signal detection performances. Methods: We used a validated reference set containing 399 true and false drug-event pairs and performed, with a frequentist and a Bayesian disproportionality method, seven types of analyses (model) for which the results were very unlikely to be related to actual differences in absolute risks of ADR. We calculated sensitivity, specificity and plotted ROC curves for each model. We then evaluated the predictive capacities of all models and assessed the impact of combining such models with the number of positive SDR for a given drug-event pair through binomial regression models. Results: We found considerable variability in disproportionality analysis results, both positive and negative SDR could be generated for 60% of all drug-event pairs depending on the model used whatever their truthfulness. Furthermore, using the number of positive SDR for a given drug-event pair largely improved the signal detection performances of all models. Conclusion: We therefore advocate for the pre-registration of protocols and the presentation of a set of secondary and sensitivity analyses instead of a unique result to avoid selective outcome reporting and because variability in the results may reflect the likelihood of a signal being a true adverse drug reaction.

High prevalence of spin was found in pharmacovigilance studies using disproportionality analyses to detect safety signals: a meta-epidemiological study.

OBJECTIVE: To systematically review and appraise misinterpretation of pharmacovigilance disproportionality analysis results in published studies. STUDY DESIGN AND SETTING: We randomly selected 100 studies that performed disproportionality analyses and indexed in Medline identified during a systematic literature search. Titles, abstracts and main texts (results, discussion and conclusion) were evaluated for spin independently by two reviewers. Spin in pharmacovigilance studies was classified according to three main categories: inappropriate interpretation, inappropriate extrapolations and misleading reporting. RESULTS: Of the 100 studies evaluated, we found that 63%, 56% and 51% had at least one type of spin in their abstract, main text or conclusion respectively, and 40% used causal language to interpret their results in the abstract or conclusion. Spin in titles and results were exclusively represented by inappropriate interpretations of findings (12% and 21% respectively), with terms such as "risk of" or "risks associated with" or results erroneously presented as regular Odds Ratios. Spin in discussion sections mostly concerned inappropriate interpretations (38%)and misleading reporting (12%). Misleading reporting, notably failing to acknowledge the limitations of disproportionality analyses, was the most frequent type of spin in abstracts (55%) and conclusion sections (37%). CONCLUSION: We found that spin is frequent in publications of pharmacovigilance disproportionality analyses, notably in abstracts. This consisted notably in an over-interpretation of the results suggesting a proven causative link between a drug use and the risk of an event.

[Thirty years of nefopam abuse in France]. / Trente ans d'abus de néfopam en France.

AIM OF THE STUDY: The use of nefopam is constantly increasing in France. The objectives of this study were to quantify the intensity of the drug dependence signal, to identify the populations at risk and the risk factors of dependence. METHODS: All serious and non-serious cases of misuse, abuse, drug dependence, overdose and withdrawal syndrome reported to the French Addictovigilance Network since 1988 were reviewed. An analysis of nefopam reimbursement data from the French national EGB (échantillon généraliste des bénéficiaires) database for the period 2006-2017 was also performed. RESULTS: The drug dependence profile of nefopam is close to that of a psychostimulant. Our literature review and the analysis of spontaneous reports confirm the risk of abuse and dependence of nefopam. In addition to a frequent psychiatric history (depression, psychosis, anxiety), nearly half of the patients also present addictive disorders, including more than one-third with opioid-dependence. In almost half of the 120 reported cases, the main adverse reaction was dependence and the frequency of serious effects was greater than 40%. In nearly 70% of the reported cases, the use was associated with chronic pain, which might explain the prolonged use. Moreover, the analysis of data on the reimbursement of nefopam in the general population showed that one French person out of two, having a prescription for nefopam, presented chronic pain. However, nefopam is only indicated in the treatment of acute painful conditions. Although it does not seem to be associated with a greater risk of abuse or dependence, taking the drug orally is another very frequent off-label use that needs to be regulated. CONCLUSION: In France, the prescription of nefopam outside of its marketing authorization is regrettable, because it contributes to the development of abuse and drug dependence.