Myeloneuropathy induced by recreational nitrous oxide use with variable exposure levels.

BACKGROUND AND PURPOSE: Although several case series have described nitrous-oxide-associated neurological disorders, a comprehensive assessment of exposure characteristics (e.g., time to onset, level of exposure) in substance abusers has not been performed. The aim of this study was to describe the onset patterns of recreational use of nitrous-oxide-induced neurological disorders. METHODS: All cases of neurological disorders related to nitrous oxide recreational use reported to the Hauts-de-France addictovigilance center between January 2019 and August 2020 were selected. Only cases requiring hospitalization with informative data to perform the nitrous oxide causality assessment were included. RESULTS: A total of 20 cases from five hospitals were included. The male-to-female ratio was 6:1 and the median age was 19 years (range 16-34). The neurological presentation (myeloneuropathy 64%, 7/11; sensorimotor neuropathy 36%, 4/11) included for all patients gait disorders due to proprioceptive ataxia and limb hypoesthesia. The median dose used per occasion was 100 cartridges (range 5-960; n = 19). The median time from the start of nitrous oxide use to the onset of neurological symptoms was 6 months (range 0.7-54; n = 16). The cumulative dose was significantly higher in patients with damage to all four limbs than in patients with lower limb symptoms only (p = 0.042). CONCLUSIONS: A low intermittent exposure may be sufficient to cause neurological damage in some subjects, suggesting that, at the population level, there is no safe exposure to nitrous oxide in recreational settings. The severity of neurological impairment could increase once used at high doses and for prolonged durations of nitrous oxide.

[Pharmaceutical cognitive doping in students: a chimeric way to get-a-head?] / Dopage cognitif chez les étudiants : un moyen chim(ér)ique de s'en mettre plein la tête ?

For students, the pressing demands for memorization, top-level performance, and peer competition create an environment favorable for pharmaceutical cognitive doping behavior. We aimed to describe recent practices and the benefit / risk ratio of such behavior and to discuss the issues at stake. The prevalence of pharmaceutical cognitive doping among students has been reported from 1.3% to 33% across studies, with variations depending on country and definition of pharmaceutical cognitive doping. The therapeutic classes most frequently cited as being diverted for doping purposes are psychostimulants and nootropics (methylphenidate, modafinil, piracetam), corticosteroids, sedative drugs and beta-blockers. Some illegal substances such as cannabis, amphetamines and cocaine are also consumed in order to boost mental function. Finally, over-the-counter products, such as caffeine-based tablets or energy drinks, or alcohol, are also widely used by students whose motivations involve enhanced performance, concentration, memory, and staying awake during the revision and exam period. However, the expected (often fantasized) effectiveness of these products does not correspond to the reality of a modest controversial impact on cognitive performance. There appears to be an emerging profile of the student more inclined to doping behavior. Cognitive doping thus raises the question of its regulation, opening a debate opposing, on one hand, individual freedom and supposed collective benefits and, on the other hand, health consequences, educational (in)equality, and the risk of tarnished academic success. Strengthening school and university medicine, through prevention campaigns and the identification of subjects at risk, is essential to limit the extent, risk, and damages associated with such practices.

Pharmaceutical cognitive doping in students: A chimeric way to get-a-head?

For students, the pressing demands for memorization, top-level performance, and peer competition create an environment favorable for pharmaceutical cognitive doping behavior. We aimed to describe recent practices and the benefit/risk ratio of such behavior and to discuss the issues at stake. The prevalence of pharmaceutical cognitive doping among students has been reported from 1.3% to 33% across studies, with variations depending on country and definition of pharmaceutical cognitive doping. The therapeutic classes most frequently cited as being diverted for doping purposes are psychostimulants and nootropics (methylphenidate, modafinil, piracetam), corticosteroids, sedative drugs and beta-blockers. Some illegal substances such as cannabis, amphetamines and cocaine are also consumed in order to boost mental function. Finally, over-the-counter products, such as caffeine-based tablets or energy drinks, or alcohol, are also widely used by students whose motivations involve enhanced performance, concentration, memory, and staying awake during the revision and exam period. However, the expected (often fantasized) effectiveness of these products does not correspond to the reality of a modest controversial impact on cognitive performance. There appears to be an emerging profile of the student more inclined to doping behavior. Cognitive doping thus raises the question of its regulation, opening a debate opposing, on one hand, individual freedom and supposed collective benefits and, on the other hand, health consequences, educational (in)equality, and the risk of tarnished academic success. Strengthening school and university medicine, through prevention campaigns and the identification of subjects at risk, is essential to limit the extent, risk, and damages associated with such practices.

The Place of Antipsychotics in the Therapy of Anxiety Disorders and Obsessive-Compulsive Disorders.

PURPOSE OF REVIEW: The purpose of this review was to assess and present the findings up to this date on the efficacy of antipsychotics in the treatment of generalized anxiety disorders (GAD), social anxiety disorders (SAD), panic disorders (PD), and obsessive-compulsive disorders (OCD), mostly based on published randomized controlled trials (RCTs) or on open-label studies when RCT were lacking. RECENT FINDINGS: Quetiapine could be recommended in patients with GAD. The efficacy of aripiprazole in two open-label studies on patients with antidepressant-refractory GAD should be assessed in RCTs. Despite preliminary positive results in open studies, there are currently no strong evidence for the effectiveness of antipsychotics in refractory SAD and in refractory PD. Conversely, risperidone and aripiprazole can be used for the treatment of refractory OCD as augmentation agents to antidepressants. Contrary to SAD and PD, this review found evidence for the use of second-generation antipsychotics in GAD and OCD. Otherwise, first-generation antipsychotics cannot be recommended in anxiety disorders and OCD.

Assessing alcohol versus baclofen withdrawal syndrome in patients treated with baclofen for alcohol use disorder.

Baclofen is a γ-aminobutyric acid B (GABA-B) receptor agonist that is approved for spasticity. Recently, the off-label use of baclofen for alcohol use disorder (AUD) has increased. However, baclofen is known to induce a neuroadaptation process, which may be identified by the occurrence of a specific baclofen withdrawal syndrome (BWS), that is, confusion, agitation, seizures, and delirium. The same set of symptoms characterizes alcohol withdrawal syndrome (AWS), which could lead to mistaking BWS for AWS in some situations. We report the cases of 3 patients under a chronic baclofen treatment for AUD. The patients emergently presented with a clinical state of confusion that was initially diagnosed and treated as AWS, with limited effect of benzodiazepines. Retrospectively, using a validated algorithm for assessing drug-induced withdrawal, we determined that all of these clinical cases were consistent with BWS. Both AWS and BWS should be considered in the case of acute confusion or delirium occurring in patients treated with baclofen for AUD. Moreover, further research should investigate to what extent GABA-A and GABA-B induce shared or distinct neuroadaptation processes and withdrawal syndromes.

Could psychostimulant drug use among university students be related to ADHD symptoms? A preliminary study.

We aimed to explore if psychostimulant use among student could be linked to attention deficit-hyperactivity disorder (ADHD) symptoms using a self-administered questionnaire sent by email to French students in 2021. Participants were asked about their psychostimulant use and the presence of ADHD symptoms using the Wender Utah Rating Scale and the Adult Self-Report Scale. Among the 4431 respondents, the prevalence of psychostimulant use was concerning and significantly associated with ADHD symptoms. This association could be related to undiagnosed ADHD or to psychobehavioral impairments induced by psychostimulant use underlining the need of ADHD screening and targeted prevention measures.

Factors associated with the use of benzodiazepine and opioid prescription drug in the student population: a cross-sectional study.

The misuse of benzodiazepines and opioid medications is frequent in students. To improve our understanding of this behavior, we aimed to identify factors associated with separate and concomitant use of these substances. Anonymous self-reported questionnaires were e-mailed to students enrolled at a French university between March and July 2021, covering: sociodemographic characteristics, academics, psychoactive substance use, ADHD symptomatology (adulthood and childhood), and psychiatric/psychological or addiction follow-up. Factors associated with the use of benzodiazepines and opioid medications included female sex (OR = 1.41 [1.08; 1.86]) and OR = 1.38 [1.06; 1.79], respectively), older age (OR = 1.65 [1.04; 2.6] and OR = 2.17 [1.4; 3.36], respectively), current psychiatric/psychological follow-up (OR = 6.53 [5.18; 8.24] and OR= 1.5 [1.12; 2.0], respectively), ADHD symptomatology (OR= 2.33 [1.71;3.16] and OR= 1.61 [1.15; 2.24], respectively), polyconsumption (tobacco use for benzodiazepine users, OR = 1.38 [1.04; 1.82]; alcohol use OR = 1.67 [1.17; 2.39] and tobacco use OR = 1.62 [1.23; 2.14] for opioid users). These factors were even more strongly associated with the concomitant use of benzodiazepines and opioid medications: older age (OR = 3.64 [2.22; 5.99]), female sex (OR = 1.54 [1.1; 2.14]), grade repetition (OR = 1.7 [1.14; 2.54]), psychiatric/psychological follow-up (OR = 4.51 [3.35;6.06]), ADHD symptomatology (OR = 5.3 [3.69; 7.63]), polyconsumption (tobacco use OR = 2.05 [1.39; 3] and cannabis use, OR = 2.07 [1.97; 4.16]. The factors associated with the use of benzodiazepines and prescription opioids identified in this study could lead to the development of targeted prevention methods.

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.

An overview of the use of psychoactive substances among students at the University of Lille during the COVID-19 health crisis: Results of the PETRA study.

OBJECTIVES: Students represent a population at risk for substance abuse. That risk may have been exacerbated by the COVID-19 pandemic. We aimed to describe substance abuse among students and to compare consumption according to the university field. METHODS: A self-administered questionnaire was sent by email to all students at the University of Lille, France, between March and July 2021. This anonymous questionnaire included questions about sociodemographic characteristics, university courses and the use of psychoactive substances (frequency, reasons, routes of administration) since the first university year. RESULTS: Among the 4431 students who responded (response rate 6.1%), eighty percent declared having used alcohol since the first university year, 34% cannabis, 15.4% benzodiazepines, 14.7% opioid drugs, 7.5% cocaine, 6.8% nitrous oxide and 6.5% MDMA. More than 20% of the users of cannabis, benzodiazepines, amphetamines and cocaine reported having already felt dependent. Recreational use was described by more than 10% of benzodiazepine or opioid drug users. Nitrous oxide use was significantly more frequent in the health and sport field (p < 0.001). Tobacco, benzodiazepine, cannabis and MDMA uses were significantly more frequent in the humanities and social sciences/art, language and literature fields (p < 0.001). CONCLUSION: Prevention measures focusing on alcohol, cannabis, illicit psychostimulants, nitrous oxide and prescription drugs are required in the student population.

[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.

A revisited version of the disputatio for pharmacological training: An educational study.

OBJECTIVE: The disputatio is a pedagogical method existing since the Middle-Ages where students had to debate about a question asked by a "master", exercising their thinking and oratory skills. To move away from traditional vertical teaching methods, the disputatio has been revived by pharmacologists. Thus, for almost three successive years, several groups of young French pharmacologists and therapists confronted their ideas concerning a medical question at a therapeutic impasse. The aim here is to describe the initial feedback received from participants. METHODS: An anonymous questionnaire was sent by email in May 2023 to the participants of the different disputationes of 2019, 2022 and 2023. Participants were asked about different aspects of their feelings before, during and after the disputatio, using the 5-point Likert scale. They were also asked to describe the event in 2 to 5 words. Finally, participants could leave their comments in a free-field and were asked to give an overall satisfaction score out of 10. RESULTS: Out of the 39 participants, 27 (69.2%) answered the questionnaire. Although 50% of respondents reported a feeling of anxiety before participating, most enjoyed the expert talks as well as working with people they did not know. Besides, over 66% reported having underestimated the skills they could share with colleagues from different backgrounds. Over 55% of respondents reported progress in methodology, and over 83% in pharmacology and/or therapeutics. Participants reported an overall satisfaction score of 8.6/10, and the main terms used to describe the event were "sharing", "enriching" and "meeting". CONCLUSION: The disputatio is an innovative training program whose pedagogical and human values were underlined by most of the participants. Beyond pharmacology and therapeutics, the principle of disputatio could be extended to other disciplines, spanning the centuries.

Comparison of biomarker for diagnosis of nitrous oxide abuse: challenge of cobalamin metabolic parameters, a retrospective study.

BACKGROUND: Recreational use of nitrous oxide (N2O) leads to neurological disorders including combined subacute degeneration of spinal cord, psychological disorders, and thrombosis. Serum or urine N2O assays could not be routinely performed. Hence, it is necessary to investigate other biological markers such as metabolic markers. We aimed here to challenge the three main biological markers used for the diagnosis of nitrous oxide abuse as total vitamin B12, homocysteine, and methylmalonic acid. METHODS: We retrospectively collected clinical and biological data from 52 patients with known, documented chronic N2O abuse and associated clinical signs (peripheral neuropathy disability score or thrombosis event). Sera and plasma total vitamin B12, methylmalonic acid (MMA), and homocysteine were performed to identify the most specific marker of chronic N2O intoxication and related clinical outcomes. RESULTS: Plasma homocysteine was almost consistently increased in case of N2O chronic consumption, whereas MMA increase and total vitamin B12 decrease are not systematically found. Our results showed that none of the markers are correlated with levels of N2O consumptions. However, homocysteine and MMA are correlated with clinical severity, but MMA seems to be a better marker of clinical severity. CONCLUSION: There is no specific marker of nitrous oxide abuse according to levels of consumption, total vitamin B12 decrease could not be used either as consumption or as severity marker. However, we showed that homocysteine is consistently increased and could be used as marker of recent N2O consumption. On the other hand, we showed that MMA could be used as a marker of clinical gravity.

Long-term cognitive impairments following COVID-19: a possible impact of hypoxia.

BACKGROUND: Cognitive and emotional disorders frequently persist after recovery from the acute symptoms of COVID-19; possible explanations include pneumonia-induced hypoxia, infection of the central nervous system, and microstrokes. The objective of the present study was to characterize the impact of hypoxia on the cognitive and psychological profile following COVID-19. METHODS: Sixty-two patients with COVID-19 were enrolled in a cross-sectional study and divided into two groups based on disease severity: outpatients with no pulmonary complications vs. inpatients with hypoxemic pneumonia having received oxygen therapy. All the participants underwent a comprehensive neuropsychological evaluation that included depression, anxiety, fatigue, sleepiness, attentional, memory and executive processes, and social cognition. For the inpatients, we also collected laboratory data (blood gas, blood glucose, fibrin, fibrinogen, D-dimer, and C-reactive protein). RESULTS: Cognitive disorders was found in patients with COVID-19: at least 18% had an impairment of memory and 11% had attentional dysfunctions. A high level of fatigue (90% of the patients), anxiety (52%), and depression (50%) was also observed. The impairments in attentional (p < 0.001 for omission and commission in CPT 3) and memory (p < 0.003 for Index Cue Efficiency from free and cue selected reminding test) functions were greater in COVID-19 inpatients that in COVID-19 outpatients. In contrast, levels of fatigue, depression, and anxiety were similarly high in both groups. CONCLUSIONS: These findings might help to improve the management of COVID-19 patients as a function of the disease severity in particular for patients with hypoxia.

What is the potential for abuse of lisdexamfetamine in adults? A preclinical and clinical literature review and expert opinion.

INTRODUCTION: Lisdexamfetamine dimesylate (LDX) is a prodrug approved for attention deficit/hyperactivity disorder and for moderate-to-severe binge eating disorder in adults in some countries. AREA COVERED: We aimed to specify the abuse potential of LDX in adults, using a review of pharmacokinetic/pharmacodynamic (PK/PD), animal, clinical, and pharmaco-epidemiological studies, through a PubMed search since inception until May 2021 using the following keywords: "lisdexamfetamine AND ('misuse' OR 'abuse' OR 'diversion' OR 'addiction')". EXPERT OPINION: Most of the studies highlighted a longer Tmax than dexamphetamine leading to a delayed onset of effects and a decreased Cmax. These PK parameters were often associated with a diminished feeling of euphoria, in comparison to immediate-release dexamphetamine. The potential for abuse was also limited by the prodrug property of LDX, thus reducing the risk of misuse. Nevertheless, all the data were not convergent, as some authors reported similar Cmax for LDX and dexamphetamine and reinforcing properties with a dose-dependent effect. Epidemiological studies found that abuse rates of LDX were substantially lower than those of immediate-release dexamphetamine. Overall, although LDX abuse seems possible, we did not find evidence concerning current safety signal. However, more long-term pharmaco-epidemiological studies are still needed to confirm this finding.

Effects of acute ethanol and/or diazepam exposure on immediate and delayed hippocampal metabolite levels in rats anesthetized with isoflurane.

Alcohol and benzodiazepines are psychoactive substances frequently associated in voluntary drug intoxications that share common mechanisms of action, including facilitation of GABAergic transmission. This study aimed to assess the separate and combined effects of ethanol and diazepam acute exposure on hippocampal metabolite levels, as well as on delayed cognitive performance, in rats anesthetized with isoflurane. Adult male Wistar rats received one intraperitoneal injection containing either saline solution ("CTL" group, N = 15), a 5-mg/kg dose of diazepam ("DIA" group, N = 16), a 2-g/kg dose of ethanol ("EtOH" group, N = 18), or a 5-mg/kg dose of diazepam + a 2-g/kg dose of ethanol ("DIA + EtOH" group, N = 24). The levels of brain metabolites in the hippocampal region were assessed using in vivo magnetic resonance spectroscopy (MRS) before and after injection. Behavioral testing, including working memory and visual recognition memory assessment, was performed at week 3, while a new MRS acquisition was conducted 4 weeks after the injection. In the hour following acute exposure, a decrease in glutamate levels was found in the DIA + EtOH group only. Four weeks after injection, a decrease in GABA and glutamate levels and an increase in NAA levels were found in the EtOH group only. No significant between-group differences were found in the behavioral assessment. While the initial decrease in glutamate levels in the DIA + EtOH group suggests an early potentiation effect between ethanol and diazepam, the long-term modifications found only in the EtOH group suggest a possible downregulation of ethanol's effect by diazepam at 4 weeks.

Antipsychotic prescribing practices in real-life (APPREAL study): Findings from the French National Healthcare System Database (2007-2017).

Background: Antipsychotics are used in a large variety of psychiatric and neurological disorders; investigating their use in real life is important to understand national prescribing practices, as well as to determine the levels of patient adherence. Methods: Using a 1/97e random sample (General Sample of Beneficiaries, EGB) of the French health insurance reimbursement database, we conducted a historical cohort study on the 2007-2017 period. The aim was to describe the sociodemographic characteristics of patients, the types of antipsychotics dispensed, the types of prescribers, the mean doses and average durations of treatment, the co-dispensed medications, and the levels of adherence to treatment. To exclude punctual uses of antipsychotics, we selected only patients with a continuous dispensing of the same antipsychotic over at least 3 months. Results: In total, 13,799 subjects (1.66% of the EGB sample) were included (56.0% females; mean age 55.8 ± 19.4 years). Risperidone (19.3%), cyamemazine (18.7%), olanzapine (11.9%), tiapride (8.8%), and haloperidol (7.5%) were the five most prescribed antipsychotics. 44.9% of prescriptions were written by general practitioners, 34.1% by hospital practitioners, and 18.4% by private-practice psychiatrists. On average, the mean dispensed doses were relatively low, but the variation range was large. Long-acting forms were used in 5.4% of the sample, and clozapine in 1.3%. 34.2% of patients received more than one antipsychotic, and almost 15% were prescribed at least three concomitant antipsychotics. Paliperidone and clozapine were associated with the highest levels of adherence, and risperidone and haloperidol with the lowest ones. Conclusion: An important heterogeneity of antipsychotic prescribing practices was observed in France. The rate of use of long-acting antipsychotics was low, whereas multiple antipsychotic prescriptions were frequent.

Pharmacotherapy of substance use disorders in the neuroscience-based nomenclature (NbN).

In the field of substance use disorders (SUDs), medications are frequently labeled according to their main symptomatic effect (e.g., "anticraving drugs") or according to imprecise and sometimes old concepts related to treatment strategies (e.g., "replacement therapies", "antabuse drugs", or "substitution treatments"). By contrast, the neuroscience-based nomenclature (NbN) offers a clearer and more consistent rationale, according to which the main element of classification is based on the pharmacological mode of action of the medication. This review aims to display the different approved treatments used in SUDs, and to discuss the pros and cons of using this new conceptual framework in the field of addiction. According to the NbN classification, medications approved in the different SUDs can be classified in the different following categories: 1) nicotinic drugs; 2) GABAergic drugs; 3) opioid drugs; and 4) others. More specifically, medications can be distinguished between whether they mimic the same pharmacological action of the "substance" whose use should be stopped or reduced, or whether they target other more general pharmacological systems, that are supposed to be common to all SUDs, as they reflect the "universal" addiction process. The NbN offers obvious advantages, compared with previous classifications. In particular, it allows to no longer mix drugs with very different pharmacological targets under the same label. The main limitation of the NbN, when applied to psychopharmacology in general, and to SUDs medications in particular, is that drugs frequently have a "dirty" action, with multiple pharmacological targets. In this respect, it may be hard to classify drugs according to the NbN classification, without making the individual profile of each medicine more complex.