Altered States and Social Bonds: Effects of MDMA and Serotonergic Psychedelics on Social Behavior as a Mechanism Underlying Substance-Assisted Therapy.

There has been renewed interest in the use of 3,4-methylenedioxy-methamphetamine (MDMA) and serotonergic psychedelics in the treatment of multiple psychiatric disorders. Many of these compounds are known to produce prosocial effects, but how these effects relate to therapeutic efficacy and the extent to which prosocial effects are unique to a particular drug class is unknown. In this article, we present a narrative overview and compare evidence for the prosocial effects of MDMA and serotonergic psychedelics to elucidate shared mechanisms that may underlie the therapeutic process. We discuss 4 categories of prosocial effects: altered self-image, responses to social reward, responses to negative social input, and social neuroplasticity. While both categories of drugs alter self-perception, MDMA may do so in a way that is less related to the experience of mystical-type states than serotonergic psychedelics. In the case of social reward, evidence supports the ability of MDMA to enhance responses and suggests that serotonergic psychedelics may also do so, but more research is needed in this area. Both drug classes consistently dampen reactivity to negative social stimuli. Finally, preclinical evidence supports the ability of both drug classes to induce social neuroplasticity, promoting adaptive rewiring of neural circuits, which may be helpful in trauma processing. While both MDMA and serotonergic psychedelics produce prosocial effects, they differ in the mechanisms through which they do this. These differences affect the types of psychosocial interventions that may work best with each compound.

Acute psychotropic, autonomic, and endocrine effects of 5,6-methylenedioxy-2-aminoindane (MDAI) compared with 3,4-methylenedioxymethamphetamine (MDMA) in human volunteers: A self-administration study.

The acute psychoactive, autonomic, and endocrine effects of the new psychoactive substance (NPS) 5,6-methylenedioxy-2-aminoindane (MDAI; 3.0 mg/kg, range 180-228 mg) were investigated in six healthy volunteers (four males, two females) in a non-blinded fashion without placebo. Subjective, cardiovascular, and endocrine responses were compared with two different doses of 3,4-methylenedioxymethamphetamine (MDMA) (75 mg and 125 mg) described in previously published placebo-controlled studies, which used identical outcome measures including Visual Analogue Scales (VAS), the Adjective Mood Rating Scale (AMRS), and the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale. MDAI was well tolerated and produced subjective effects comparable with those of 125 mg MDMA. MDAI increased blood pressure similar to 125 mg MDMA but did not increase heart rate or body temperature. MDAI increased cortisol and prolactin levels and could be detected in serum about 20 min post ingestion and remained detectable at least for 4 days. In urine, MDAI was detectable over a period of at least 6 days. Further clinical investigations are warranted to assess whether MDAI could serve as drug with medicinal properties.

Self-discharge during treatment for acute recreational drug toxicity: an observational study from emergency departments in seven European countries.

BACKGROUND: Self-discharge is a risk factor for readmission and excess mortality. We assess the rate of self-discharge from the emergency department (ED) among presentations for acute recreational drug toxicity and identify factors associated with self-discharge. METHODS: From the Euro-DEN Plus database of presentations to the ED with acute recreational drug toxicity, we extracted data from 11 centres in seven European countries from 2014 to 2017. Self-discharge was defined as taking one's own discharge or escaping from the ED before being medically cleared. We used multiple logistic regression analyses to look for factors associated with self-discharge. RESULTS: Among 15,135 included presentations, 1807 (11.9%) self-discharged. Self-discharge rates varied from 1.7 to 17.1% between centres. Synthetic cannabinoids were associated with self-discharge, adjusted odds ratio 1.44 (95% confidence interval 1.10-1.89), as were heroin, 1.44 (1.26-1.64), agitation, 1.27 (1.10-1.46), and naloxone treatment, 1.27 (1.07-1.51), while sedation protected from self-discharge, 0.38 (0.30-0.48). CONCLUSION: One in eight presentations self-discharged. There was a large variation in self-discharge rates across the participating centres, possibly partly reflecting different discharge procedures and practices. Measures to improve the management of agitation and cautious administration of naloxone to avoid opioid withdrawal symptoms may be approaches worth exploring to reduce self-discharge.

A non-hallucinogenic LSD analog with therapeutic potential for mood disorders.

Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT2A, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT2A ß-arrestin recruitment and internalization in vitro and does not induce tolerance in vivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT2A-selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications.

Severity of emergency department presentations due to acute drug toxicity in Europe: a longitudinal analysis over a 6-year period (2014-2019) stratified by sex.

OBJECTIVE: To investigate whether the severity of acute recreation drug toxicity presentations to emergency departments (EDs) in Europe has changed in recent years and to uncover potential sex differences. DESIGN: We analysed presentations to 36 EDs in 24 European countries relating to acute recreational drug toxicity, with separate analysis for presentations involving lone use of cannabis, cocaine, and heroin. As severity markers, we calculated rates of hospitalization, admission to ICU, intubation, and death by annual quarters between 2014 and 2019. Trends on severity over time were estimated by logistic regression. Differences between men and women were assessed by interaction. Sensitivity analysis was performed including only EDs that provided data for all 24 quarters. Analyses of intoxications taken altogether were adjusted by age and sex, while of lone intoxications being also adjusted by ethanol co-ingestion. RESULTS: There were 43 633 presentations (median age = 31 years, interquartile range = 25-40 years, men = 76.5%) resulting in 10 344 hospitalizations (23.9%), 2568 ICU admissions (5.9%), 1391 intubations (3.2%), and 171 deaths (0.39%). Hospitalization, ICU admission and death did not differ by sex, but intubation was more frequent in men (3.4% vs. 2.3%, P < 0.001). No significant changes in the severity of drug intoxications over time were found when considered altogether, neither for lone cannabis (n = 4264) nor cocaine (n = 3562). Conversely, significant increases in hospitalization [odds ratios (OR) = 1.023, 95% confidence interval (CI) = 1.004-1.041], ICU admission (OR = 1.080, 95% CI = 1.042-1.118) and in intubation (OR = 1.049, 95% CI = 1.001-1.099) were detected for lone heroin presentations (n = 1997). Sensitivity analysis (32 245 presentations, 14 EDs, 9 countries) confirmed the overall absence of changes in severity markers (except for death rate, which significantly decreased by quarter: OR = 0.968, 95% CI = 0.943-0.994). Additionally, it suggested an increased risk over time of intubation for cocaine (OR = 1.068, 95% CI = 1.009-1.130) and confirmed the increased risk of ICU admission for heroin (OR = 1.058, 95% CI = 1.013-1.105). Changes in severity over time did not differ according to sex in the main analysis of the whole cohort, while a significantly higher decrease in risk of death in men was found in the sensitivity analysis (OR = 0.894, 95% CI = 0.825-969 vs. OR = 0.949, 95% CI = 0.860-1.048; P interaction = 0.042). CONCLUSIONS: The severity of presentations to European EDs remained mainly unchanged during 2014-2019, but the risk of death may have decreased. Conversely, intubation in lone cocaine and ICU admission in lone heroin intoxications have increased. Although men and women exhibited a similar pattern over the period for the majority of comparisons, our data suggest that women exhibited a smaller decrease of the overall risk of death.

Differences in clinical features associated with cannabis intoxication in presentations to European emergency departments according to patient age and sex.

OBJECTIVE: To investigate if clinical features associated with acute cannabis intoxication in patients presenting to Emergency Departments for medical assistance differ according to patient age and sex. METHODS: We analysed presentations in the Euro-DEN Plus dataset from 2014 to 2019 in which cannabis was the only drug involved (except for alcohol), and age, sex and alcohol co-ingestion had been recorded. Age was considered as categorical (five groups; <20, 20-29, 30-39, 40-49 and ≥50 years), and sex as binary variable (male/female). We evaluated 12 key clinical features recorded during emergency department (ED) care. Risks of presenting with each of these clinical features according to patient age and sex were calculated by logistic regression models, and adjusted for sex, age and alcohol co-ingestion. RESULTS: 4,268 of 43,633 Euro-DEN presentations (9.8%) fulfilled the inclusion criteria (median age: 26 years (IQR = 20-34), 70% male, 52% co-ingested alcohol). The frequency of clinical features was: anxiety 28%, vomiting 24%, agitation 23%, palpitations 14%, reduced consciousness 13%, acute psychosis 9%, hallucinations 9%, chest pain 7%, headache 6%, hypotension 4%, hypertension 3% and seizures 2%. Patients younger than 20 years more frequently had vomiting (34.7% of cases), reduced consciousness (21.5%), and headache (10.8%); and less frequently acute psychosis (5.5%). Patients older than 49 years more often had hypotension (6.5%) and less frequently vomiting (20%), anxiety (14%), agitation (14%) and reduced consciousness (10%). Males more frequently presented with hypertension (3.7 vs. 1.5%; OR = 2.311, 95%CI = 1.299-3.816), psychosis (10.4 vs 6.3%; 1.948, 1.432-2.430), chest pain (8.1 vs 4.5%; 1.838, 1.390-2.430) and seizures (2.5 vs 1.4%; 1.805, 1.065-3.060), and less frequently with vomiting (21.8 vs 28.2%; 0.793, 0.677-0.930), anxiety (25.4 vs 32.3%; 0.655, 0.561-0.766) and hypotension (2.9 vs 5.8%; 0.485, 0.350-0.671). CONCLUSIONS: The prevalence of some clinical features typically associated with acute cannabis intoxication differed according to age and sex. The causes for these differences should be further investigated in order to better understand the pathophysiology of cannabis-related acute toxicity, and they may be relevant particularly for developing prevention campaigns and for treatment in specific sex and/or age groups.

Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants.

BACKGROUND: LSD and psilocybin are increasingly used in phase I trials and evaluated as therapeutic agents for mental disorders. The phenomenon of reoccurring drug-like experiences after the acute substance effects have worn off was described for both substances and especially attributed to LSD. According to the DSM-V, the persisting and distressing manifestation of these experiences is called hallucinogen-persisting perception disorder (HPPD). Data on both conditions is very limited. OBJECTIVE: This study aims to provide descriptive data on reoccurring drug-like experiences after the administration of LSD and psilocybin in controlled studies with healthy participants. METHODS AND MATERIALS: Data from 142 healthy subjects enrolled in six double-blinded, placebo-controlled, randomized cross-over studies were analyzed. In total, 60 subjects received LSD; 27 subjects received LSD, MDMA, and D-amphetamine; 31 subjects received LSD and psilocybin; and 25 subjects received psilocybin and escitalopram. At the end-of-study visit (mean 39.8 days after last study session, SD 37.2), subjects were asked for any reoccurring drug effects since the initial substance effects had worn off. Those reporting reoccurring perception changes more than 24 h after administration were contacted for follow-up (mean follow-up duration: 31.2 months, SD 28.6). RESULTS: Thirteen out of 142 subjects reported reoccurring drug-like experiences (LSD: seven, psilocybin: two, both: four). The reported phenomena were predominantly mild and perceived as neutral to pleasant. Flashbacks were mostly of visual nature, lasted for seconds to minutes, and occurred within a week after the last drug administration. Two subjects reported distressing experiences that subsided spontaneously. One subject reported brief and pleasant visual perception changes which reoccurred for 7 months. None of the subjects reported impairment in their daily lives. None of the cases met DSM-V criteria for HPPD. CONCLUSION: Reoccurring drug-like experiences after the administration of LSD and psilocybin are a common phenomenon occurring in up to 9.2% of healthy subjects (7.8% for LSD, 8.3% for psilocybin and 14.3% if both substances are administered). Additionally, our work suggests that flashback phenomena are not a clinically relevant problem in controlled studies with healthy participants.

Gastrointestinal bleeding during anticoagulation with direct oral anticoagulants compared to vitamin K antagonists.

Aim: Patients receiving oral anticoagulants with vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) have an increased risk of gastrointestinal bleeding (GIB). We compared cases of GIB associated with VKAs and DOACs in terms of risk factors, scores, timing, location, severity, and outcome. Methods: Data from patients treated at a university hospital in Switzerland for GIB under VKA and DOACs between 2012 and 2018 were analyzed in this investigator-driven, retrospective, single-center study. Results: A total of 248 patients (110 males; median age, 80 years; 134 VKA, 114 DOAC) were included. No significant differences in age, weight or sex were observed. The propensity of the VKA group for risk factors such as comorbidities, interacting medications, or a high risk for bleeding (HAS-BLED score) was higher than that of the DOAC group. 56% of the VKA-treated patients had a supratherapeutic INR, and 25% in the DOAC group received an unlicensed dose. Significantly more patients in the DOAC group were not formally overdosed with OAC whilst receiving amiodarone compared to the VKA group (57% vs. 18%, respectively, p = 0.03). Latency between the documented start of oral anticoagulation and GIB was shorter in the DOAC group (median 3 months) than in the VKA group (median 23.5 months, p¡0.001). There were no differences in terms of location and severity of the GIB, length of hospitalization, or mortality. Conclusion: Patients taking VKAs displayed more risk factors for GIB than those taking DOACs. Treatment with DOACs was associated with early GIB and calls for increased vigilance during the first months after commencement. Co-medication with amiodarone appeared to be a risk factor for GIB in patients taking DOACs.

Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis.

Lysergic acid diethylamide (LSD) is a classic psychedelic substance that is used recreationally and investigated in psychiatric research. There are no pharmacogenetic studies on LSD. In vitro metabolic studies indicate that several cytochrome P450 (CYP) isoforms (e.g., CYP2D6, CYP1A2, and CYP2C9) are involved in LSD metabolism, but in vivo data are scarce. The present study examined the influence of genetic polymorphisms of CYP genes on the pharmacokinetics and acute effects of LSD in healthy subjects. We identified common genetic variants of CYPs (CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP2B6) in 81 healthy subjects who were pooled from four randomized, placebo-controlled, double-blind Phase 1 studies. We found that genetically determined CYP2D6 functionality significantly influenced the pharmacokinetics of LSD. Individuals with no functional CYP2D6 (i.e., poor metabolizers) had longer LSD half-lives and approximately 75% higher parent drug and main metabolite 2-oxo-3-hydroxy LSD area-under-the-curve blood plasma concentrations compared with carriers of functional CYP2D6. Non-functional CYP2D6 metabolizers also exhibited greater alterations of mind and longer subjective effect durations in response to LSD compared with functional CYP2D6 metabolizers. No effect on the pharmacokinetics or acute effects of LSD were observed with other CYPs. These findings indicate that genetic polymorphisms of CYP2D6 significantly influence the pharmacokinetic and subjective effects of LSD. Given the potential therapeutic use of psychedelics, including LSD, the role of pharmacogenetic tests prior to LSD-assisted psychotherapy needs to be further investigated.

Acute subjective effects in LSD- and MDMA-assisted psychotherapy.

BACKGROUND: Lysergic acid diethylamide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA) were used in psychotherapy in the 1960s-1980s, and are currently being re-investigated as treatments for several psychiatric disorders. In Switzerland, limited medical use of these substances is possible in patients not responding to other treatments (compassionate use). METHODS: This study aimed to describe patient characteristics, treatment indications and acute alterations of mind in patients receiving LSD (100-200 µg) and/or MDMA (100-175 mg) within the Swiss compassionate use programme from 2014-2018. Acute effects were assessed using the 5 Dimensions of Altered States of Consciousness scale and the Mystical Experience Questionnaire, and compared with those in healthy volunteers administered with LSD or MDMA and patients treated alone with LSD in clinical trials. RESULTS: Eighteen patients (including 12 women and six men, aged 29-77 years) were treated in group settings. Indications mostly included posttraumatic stress disorder and major depression. Generally, a drug-assisted session was conducted every 3.5 months after 3-10 psychotherapy sessions. LSD induced pronounced alterations of consciousness on the 5 Dimensions of Altered States of Consciousness scale, and mystical-type experiences with increases in all scales on the Mystical Experience Questionnaire. Effects were largely comparable between patients in the compassionate use programme and patients or healthy subjects treated alone in a research setting. CONCLUSION: LSD and MDMA are currently used medically in Switzerland mainly in patients with posttraumatic stress disorder and depression in group settings, producing similar acute responses as in research subjects. The data may serve as a basis for further controlled studies of substance-assisted psychotherapy.

MDMA-related presentations to the emergency departments of the European Drug Emergencies Network plus (Euro-DEN Plus) over the four-year period 2014-2017.

CONTEXT: 3,4-Methylenedioxymethamphetamine (MDMA) remains one of the most commonly used recreational drugs in Europe. Monitoring of Emergency Department (ED) presentations with acute toxicity associated with MDMA is important to determine trends in MDMA use and harms. METHODS: Data were extracted from the European Drug Emergencies Network (Euro-DEN) Plus database for all ED presentations with acute toxicity involving MDMA use, alone or in combination with other substances, between 1 January 2014 and 31 December 2017. Geographical distribution, time trends, patient demographics, clinical features, management and outcome were analysed. RESULTS: Out of 23,947 presentations, 2013 (8.4%) involved MDMA, used alone (88, 4.4%) or with other substances (1925, 95.6%). The proportion of MDMA presentations varied by country, from over 15% in France to less than 5% in Norway. For the 15 sentinel centres where data were available for all four years, MDMA-related presentations peaked in 2016 (10.4% versus 8.1% in 2015, p < 0.0001), thereafter decreasing in 2017 (8.2%, p = 0.0002). 1436 (71.3%) presentations involved males. Females were significantly younger than males (median 23 years, interquartile range, IQR, 20-27 years, versus median 25 years, IQR 21-30 years, p < 0.0001). Compared to presentations of acute toxicity with lone-use cocaine, presentations with lone-use MDMA occurred more frequently during the weekend (58.0% versus 43.9%, p = 0.02), were more frequently medically discharged directly from the ED (74.7% versus 62.4%, p = 0.03), and less frequently received sedation (43.5% versus 66.5%, p = 0.003). CONCLUSIONS: This large multicentre series of MDMA presentations to EDs showed geographical variation and changes in time trends and in patient demographics. Triangulation with data from complementary sources including seizures, prevalence of use and wastewater analysis, will enable a greater understanding of the public health implications of MDMA use in Europe.

Pharmacokinetics and phenotyping properties of the Basel phenotyping cocktail combination capsule in healthy male adults.

AIMS: We compared the phenotyping metrics of a combination capsule formulation to its individual components of the newly composed Basel phenotyping cocktail. Moreover, we investigated a reduced sampling regimen for clinical applications. METHODS: We performed in vitro experiments and a crossover pharmacokinetic study in twelve healthy male subjects to compare the Basel phenotyping cocktail capsule containing 6 cytochrome P450 (CYP) probe drugs with individual administration of the same drugs. Parent compounds and selected metabolites were determined by liquid chromatography-tandem mass spectrometry. Metabolic ratios (MR) for are under the curve (AUC) and single time point measurements and their correlation were determined. RESULTS: Experiments with human liver microsomes and primary human hepatocytes in 3D co-culture confirmed that flurbiprofen is a suitable CYP2C9 substrate. Both cocktail formulations (capsule and individual probe drug administration) were well-tolerated and yielded reproducible MRs, which were almost identical. Correlations between single time point ratios and the corresponding AUC ratios depended on the sampling time point and the concentration time curve of the probe drugs. The MR of the capsule (Spearman rank correlation coefficient, Rs : 0.77-0.97) as well as the individual components (Rs : 0.69-0.99) correlated best at 6 h post-treatment considering all 6 CYPs. Moreover, the 2-h time points of the capsule agreed suitably with the AUC; however, the MR of omeprazole could not be determined for 10 out of 12 subjects. CONCLUSION: The capsule is easy to swallow, well tolerated and provides reliable estimates for CYP activity. The optimal sampling point for the capsule formulation is 6 h after intake.

Emergency department presentations related to acute toxicity following recreational use of cannabis products in Switzerland.

BACKGROUND: Concomitant use of cannabis and other psychoactive substances is common and it is often difficult to differentiate its acute effects from those of other substances. This study aimed to characterize the acute toxicity of cannabis with and without co-use of other substances. METHODS: Retrospective analysis of cases presenting at the emergency departments of three large hospitals in Switzerland due to acute toxicity related to cannabis recreational use. RESULTS: Among 717 attendances related to acute cannabis toxicity, 186 (26 %) were due to use of cannabis alone. The median patient age was 26 years (range 14-68), and 73 % were male. Commonly reported symptoms/signs in lone-cannabis cases included nausea/vomiting (26 %), palpitations (25 %), anxiety (23 %), and chest pain (15 %); there were no fatalities and most intoxications were of minor severity (61 %). Most patients (83 %) using cannabis alone were discharged from the emergency department, 8 % were referred to psychiatric, and two (1 %) to the intensive care; severe complications included psychosis (7 %), coma (6 %), and seizures (5 %) and one patient (<1 %) required intubation. Lone-cannabis patients presented more often with palpitations, anxiety, panic attacks, and chest pain than patients in the co-use group, whereas the latter presented more often with impaired consciousness, agitation, respiratory depression and hallucinations, and were more often admitted to psychiatric or intensive care. CONCLUSION: Intoxication with cannabis alone was mostly associated with minor toxicity. Nevertheless, severe complications and cases requiring admission to intensive or psychiatric care were also reported, which indicates that intoxication with cannabis alone does not exclude considerable health risks.

[Knockout Drugs: Diagnostics in the Emergency Unit and Clinical Practice]. / Verdacht auf K.o.-Mittel: Diagnostik in der Notfallstation und Praxis.

Knockout Drugs: Diagnostics in the Emergency Unit and Clinical Practice Abstract. Every now and then, physicians are challenged with date rape drugs. If there is a suspicion of substance administration, the question of involving forensic medicine is commonly raised. In obscure situations or questionable offences, however, patients may wish for an initial diagnosis in the emergency department or the private practice. The physicians are often greatly challenged by the variety of substances, the limited analytical methods and difficulties with the interpretion of results. The major goal of this article is to present diagnostic options including their limitations. An overview of frequently involved substances is provided. Particular focus will be placed on practical aspects, including questions regarding pre-analytics and health insurance coverage.

Emergency department presentations related to abuse of prescription and over-the-counter drugs in Switzerland: time trends, sex and age distribution.

AIMS OF THE STUDY: To analyse emergency department (ED) presentations related to acute medical problems after recreational use of prescription/over-the-counter (OTC) drugs in two major Swiss hospitals in order to identify the prevalence of specific drugs, vulnerable groups, time trends and local differences which could have major public health implications. METHODS: Retrospective analysis of cases presenting with signs/symptoms consistent with acute toxicity due to recreational use of prescription/OTC drugs from May 2012 to August 2017 at the ED of the University Hospital of Bern and from October 2013 to July 2017 at the ED of the University Hospital Basel. We investigated time trends, sex differences, patient characteristics and consumption patterns within three age groups (≥16 to <36 years; ≥36 to <56 years; ≥56 years). RESULTS: During the study period, 344 cases were included out of 1715 ED attendances due to acute drug toxicity and a total of 412,557 ED presentations. The use of prescription drugs in conjunction with illegal drugs was reported in nearly half the cases. The most frequently reported prescription drugs were benzodiazepines (64%, n = 220) and methadone (13%, n = 45). Forty-eight percent (n = 166) of all presentations occurred within the youngest age group. The analysis of time trends showed a significant increase in presentations in the youngest and the oldest groups in Basel (both p <0.05), while the trend remained stable over time in Bern for all age groups. While the number of presentations remained constant over time for men and women in Bern, a significant increase was found for the female cohort in Basel (p <0.05). Patients in all age groups presented with toxicities of predominantly minor severity. CONCLUSION: The prescription/OTC drugs most frequently leading to ED presentations after recreational use were sedative substances. A large proportion of the patients belonged to the youngest age group. A significant increase in presentations was seen in the youngest and oldest age groups and within women in Basel. This information can be used to inform health care providers so that they can adapt their prevention and treatment strategies in their communities.

Sex differences in the pharmacology of itch therapies-a narrative review.

BACKGROUND: Chronic itch is the most common skin-related condition, associated with a high psychosocial and economic burden. In recent years, increasing evidence of sex differences in the perception, clinical presentation and treatment requirements of itch points towards potential benefits when using sex-adapted therapies. It is well-known that body composition, absorption, metabolism, elimination and adverse drug reactions (ADRs) differ between sexes, but only little is known about the impact of sex in the pharmacology of itch treatments, which could help to rationalise sex-adapted treatment strategies. AIM: To evaluate and review sex effects in the pharmacokinetics and /-dynamics of drugs used to treat itch. METHODS: In this narrative review we performed a PubMed and MEDLINE (Ovid) search using the terms (itch OR pruritus) AND (gender OR sex) AND (drug OR medication OR pharmacokinetics OR pharmacodynamics). Additional searches were performed for the topical and systemic drugs recommended by the European Guideline on Chronic Pruritus. RESULTS: We found numerous reports with variable levels of evidence of sex effects with respect to the pharmacokinetics and/or pharmacodynamics of 14 drug classes used for the treatment of itch, including a total of 19 systemic and 3 topical drugs. Women seem to present higher plasma levels of several drugs used in itch treatment, including tri- and tetracyclic antidepressants (e.g. doxepin, amitriptyline, mirtazapine), serotonin reuptake inhibitors (e.g. paroxetine, sertraline, fluoxetine), immunosuppressive drugs (e.g. cyclosporine, mycophenolate mofetil), serotonin receptor antagonists (e.g. ondansetron) and betablockers (e.g. propranolol). Adverse drug reactions (ADRs) were generally more common in women. Being female was reported to be an independent risk factor for QTc-prolongation associated with antihistamines and tetracyclic antidepressants. Additionally, women seem to be more prone to sedative effects of antihistamines, and to suffer from a higher frequency as well as severity of side effects with systemic calcineurin inhibitors, opioid agonists, and opioid antagonists. Women were also sensitised more often to topically applied drugs. Of note, apart from only one experimental study with capsaicin, none of these reports were designed specifically to assess the effect of sex (and gender) in the treatment of itch. DISCUSSION/CONCLUSION: Our review supports previous reports that sex is of importance in the pharmacokinetics and /-dynamics of several drugs used to treat itch although those drugs were mostly evaluated for non-itch indications. However, the results are limited by methodological limitations evident in most studies such as underrepresentation of women in clinical trials. This emphasises the need to study the impact of sex (and gender) in future itch trials to yield better outcomes and prevent ADRs in both sexes.

Microdosed midazolam for the determination of cytochrome P450 3A activity: Development and clinical evaluation of a buccal film.

Cytochrome P450 3A (CYP3A) isozymes metabolize about 50% of all marketed drugs. Their activity can be modulated up to 400-fold, which has great impact on individual dose requirements for CYP3A substrates. The activity of CYP3A can be monitored using the CYP3A substrate midazolam. To avoid pharmacological midazolam effects during phenotyping, a microdosing approach is preferred. However, the preparation of microdosed dosage forms remains a challenge. Fast dissolving buccal films are therefore proposed to facilitate this task. It was the aim of the present study to clinically evaluate a novel buccal film containing microdoses of midazolam for assessment of CYP3A activity. In a randomized, open-label crossover design, the pharmacokinetics of midazolam and its active hydroxy-metabolite, 1'­OH­midazolam, was assessed in 12 healthy volunteers after administration of single microdoses of midazolam (30 µg) as buccal film or buccal solution. The buccal film did rapidly disintegrate, was well tolerated, and no adverse events occurred. The film and the solution showed very similar midazolam plasma concentration-time profiles but were not bioequivalent according to EMA and FDA guidelines. For Cmax, AUC0-12h, and AUC0-∞ the geometric mean ratios of film to solution, with their 90% confidence intervals in parentheses, were 1.15 (1.00-1.32), 1.16 (1.04-1.28), and 1.19 (1.08-1.31), respectively. As a proxy for CYP3A activity, molar metabolic ratios of midazolam and 1'­OH­midazolam were analyzed over time, which revealed good correlations already 1 h or 2 h after application of the film or the solution, respectively. The tested midazolam buccal film is a convenient dosage form that facilitates administration of a phenotyping probe considerably and may potentially be used in special patient populations such as pediatric patients. Clinical Trials.gov Identifier: NCT03204578.

Hypersensitivity reaction with multi-organ failure following re-exposure to rifampicin: case report and review of the literature including WHO spontaneous safety reports.

BACKGROUND: True hypersensitivity reactions to rifampicin are relatively rare, nonetheless severe manifestations mostly involving a single organ have been documented. We report a case of acute multi-organ failure occurring after a medication error with re-exposure to rifampicin. CASE PRESENTATION: A 68-year old patient developed acute hypersensitivity pneumonitis, acute renal failure, acute liver failure and haemolytic anemia within hours after a second re-exposure to Rifampicin for the treatment of a hip prosthesis infection with Staphylococcus epidermidis. A recent rifampicin exposure 1 week earlier had resulted in a massive rise of CRP levels without organ manifestations. Nine years previously, the patient had developed a multi-organ hypersensitivity reaction 8 days after commencing treatment with rifampicin for pulmonary tuberculosis; and 23 years previously he had received rifampicin without problems. The organ-specific hypersensitivity reactions were largely reversible after withdrawal of rifampicin and treatment with steroids. A review of the literature and summary of WHO spontaneous safety reports is also given. CONCLUSIONS: Re-exposure to rifampicin in sensitised individuals may cause acute severe hypersensitivity reactions. Due to its indications in the management of mycobacterial and implant-associated infections, rifampicin is a drug which might be given decades apart, which poses a risk that information about previous intolerance is lost.

Pharmacokinetics of oxycodone/naloxone and its metabolites in patients with end-stage renal disease during and between haemodialysis sessions.

BACKGROUND: The pharmacokinetics of oxycodone in patients with end-stage renal disease (ESRD) requiring haemodialysis are largely unknown. Therefore, we investigated the pharmacokinetics of oxycodone/naloxone prolonged release and their metabolites in patients with ESRD during and between haemodialysis sessions. METHODS: Single doses of oxycodone/naloxone (5/2.5 or 10/5 mg) were administered in nine patients with ESRD using a cross-over design on the day of dialysis and on a day between dialysis sessions. Plasma, dialysate and urine concentrations of oxycodone, naloxone and their metabolites were determined up to 48 h post-dosing using a liquid chromatography-tandem mass spectrometry system. RESULTS: Haemodialysis performed 6-10 h after dosing removed ∼10% of the administered dose of oxycodone predominantly as unconjugated oxycodone and noroxycodone or conjugated oxymorphone and noroxymorphone. The haemodialysis clearance of oxycodone based on its recovery in dialysate was (mean ± SD) 8.4 ± 2.1 L/h. The geometric mean (coefficient of variation) plasma elimination half-life of oxycodone during the 4-h haemodialysis period was 3.9 h (39%) which was significantly shorter than the 5.7 h (22%) without haemodialysis. Plasma levels of the active metabolite oxymorphone in its unconjugated form were very low. CONCLUSIONS: Oxycodone is removed during haemodialysis. The pharmacokinetics including the relatively short half-life of oxycodone in patients with ESRD with or without haemodialysis and the absence of unconjugated active metabolites indicate that oxycodone can be used at usual doses in patients requiring dialysis.

Human Metabolome Changes after a Single Dose of 3,4-Methylenedioxymethamphetamine (MDMA) with Special Focus on Steroid Metabolism and Inflammation Processes.

The intake of 3,4-methylenedioxymethamphetamine (MDMA) is known to increase several endogenous substances involved in steroid and inflammation pathways. Untargeted metabolomics screening approaches can determine biochemical changes after drug exposure and can reveal new pathways, which might be involved in the pharmacology and toxicology of a drug of abuse. We analyzed plasma samples from a placebo-controlled crossover study of a single intake of MDMA. Plasma samples from a time point before and three time points after the intake of a single dose of 125 mg MDMA were screened for changes of endogenous metabolites. An untargeted metabolomics approach on a high-resolution quadrupole time-of-flight mass spectrometer coupled to liquid chromatography with two different chromatographic systems (reversed-phase and hydrophobic interaction liquid chromatography) was applied. Over 10 000 features of the human metabolome were detected. Hence, 28 metabolites were identified, which showed significant changes after administration of MDMA compared with placebo. The analysis revealed an upregulation of cortisol and pregnenolone sulfate 4 h after MDMA intake, suggesting increased stress and serotonergic activity. Furthermore, calcitriol levels were decreased after the intake of MDMA. Calcitriol is involved in the upregulation of trophic factors, which have protective effects on brain dopamine neurons. The inflammation mediators hydroxyeicosatetraenoic acid, dihydroxyeicosatetraenoic acid, and octadecadienoic acid were found to be upregulated after the intake of MDMA compared with placebo, which suggested a stimulation of inflammation pathways.