Impact of the UK Psychoactive Substances Act on awareness, use, experiences and knowledge of potential associated health risks of novel psychoactive substances.

AIMS: The risk of potential harms prompted the UK government to introduce the Psychoactive Substances Act in 2016. The aim of the present study was to evaluate the impact and effectiveness of this new legislation on patterns of novel psychoactive substance (NPS) awareness, use, experiences and risk awareness in a self-selected sample of UK consumers to inform education and policy. METHODS: The Bristol Online Survey was advertised on the Bluelight drug forum and social media Facebook pages and University email between 7 January and 7 February 2015 (168 responses) and 9 March to 18 September 2017 (726 responses). UK country of residence responses were extracted for analysis (SPSS). RESULTS: In a predominantly university-educated, young (< 25 years) self-selecting sample, 1 year after introduction of the legislation, NPS use (in males, under 18s, those educated to school/college level, P < .001) has increased, whilst health risk awareness has not changed and remains poor. Users are switching to sourcing NPSs via street dealers (49%) and the darknet (31%) and showing an increase in preference for the herbal NPS Salvia divinorum (P < .05). The main reasons for NPS use remain the influence of friends (69%) in a social setting and to get high (76%) usually in combination with alcohol, cannabis or ecstasy. CONCLUSION: Regulation alone, so far, has not impacted on health risk awareness, NPS drug demand and culture in our UK survey sample. Alongside regulation, NPS health promotion education (particularly in schools, colleges) is needed that addresses resilience and both the risks and beneficial effects of NPS.

An Insight into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions.

BACKGROUND: Although originally marketed as safe alternatives to the habit-forming benzodiazepines, growing numbers of zaleplon, zolpidem, and zopiclone ("Z-drugs") clinical concerns relating to their potential of abuse, dependence, and withdrawal have been reported over time. We aimed here at assessing these issues analyzing datasets of adverse drug reactions provided by the European Medicines Agency through the EudraVigilance system. METHODS: Analyzing the adverse drug reactions databases of each Z-drug, descriptive analyses have been performed on cases and proportional reporting ratios (PRRs) computed. RESULTS: An overall number of 33 240 (e.g., 23 420 zolpidem; 9283 zopiclone; and 537 zaleplon) misuse-, abuse-, dependence-, and withdrawal-related adverse drug reactions, corresponding to some 6246 unique patients given Z-drugs, were here identified. Cases were studied and described, including demographic characteristics and clinical data such as concomitant drugs, doses, routes of administration, and outcomes of the reactions (being fatalities recorded). Considering PRR values and in comparison with zopiclone, zolpidem was more frequently involved in both misuse/abuse and withdrawal issues. Zolpidem and zopiclone presented with the same dependence risk, but zopiclone was most involved in overdose adverse drug reactions. Compared with zaleplon, zopiclone presented higher dependence and overdose-related issues but slightly lower misuse/abuse and withdrawal PRR values. CONCLUSION: Current data may only represent a gross underestimate of the real prevalence of Z-drug misuse. Caution should be exercised when prescribing those molecules, especially for patients with psychiatric illnesses and/or history of drug abuse. We recommend the need to invest in proactive pharmacovigilance activities to better and promptly detect, understand, and prevent any possible misuse potential of prescribed medications.

An international survey on the awareness, use, preference, and health perception of novel psychoactive substances (NPS).

OBJECTIVE: This survey investigated the level of public awareness, preference, and motivation of novel psychoactive substances (NPS) use as well as knowledge of potential associated health risks. METHODS: A Bristol Online Survey was advertised through social media and a drug forum "Bluelight" between January 7 and February 7, 2015. RESULTS: Responses were received from 17 countries, mainly from Europe. Most responses (83%) came from university educated students. Two-thirds (65%) of the 168 respondents were aware of NPS. Awareness was significantly increased in those with bisexual or homosexual orientation (p < .05) and those in employment (p < .05). Fourteen percent of the 168 respondents were users of NPS, and use was significantly affected by age and employment (p < .01) but unaffected by level of education (p > .05). Nearly half of the NPS users perceived NPS to carry either a low risk to health (20%) or did not know whether or not they posed a health risk (29%). CONCLUSIONS: These survey data indicate that awareness of NPS and, importantly, perception of the potential health risks associated with NPS use is lacking. NPS awareness and use is higher in those in employment but is unaffected by level of education. This highlights the need for targeted drugs education intervention by policy-makers in schools and universities.

Is there a potential of misuse for Magnolia officinalis compounds/metabolites?

OBJECTIVE: Magnolia bark contains magnolol, metabolized to tetrahydromagnolol and honokiol, with both GABA-ergic/cannabimimetic activities, hence of possible attraction to vulnerable individuals/recreational misusers. METHODS: A literature review, assessment of related anecdotal online Magnolia misuse's reports and an overview of Magnolia products' online acquisition possibilities has been here described. RESULTS: No peer-reviewed papers about Magnolia abuse/misuse/dependence/addiction were identified. Conversely, from a range of websites emerged potentially 3 groups of Magnolia misusers: (a) subjects with a psychiatric history already treated with benzodiazepines, being attracted to Magnolia bark as a "natural sedative"; (b) polydrug misusers, ingesting Magnolia with a range of other herbs/plants, attracted by the GABA-ergic/cannabimimetic activities; (c) subjects naive to the misusing drugs' scenario, perceiving Magnolia as a natural dietary supplement/weight-control compound. CONCLUSIONS: To the best of our knowledge, this is the first paper commenting on the possible Magnolia derivatives' potential of misuse. Magnolia's recent increase in popularity, mainly as a sedative, may be arguably due to its peculiar pharmacological properties/acceptable affordability levels/virtually worldwide favorable legal status and customers' attraction to a product being perceived as "natural" and hence somehow "safe." Future/potent/synthetic magnolol and honokiol structural analogues could however contribute to increasing the number of synthetic GABA-ergic/cannabimimetic misusing compounds.

Methoxetamine-related deaths in the UK: an overview.

OBJECTIVE: The goal of this study is to provide an update on the data given on methoxetamine (MXE)-related fatalities that occurred in 2011-2013, presented at the Second International Conference on Novel Psychoactive Substances. METHODS: Fatalities involving MXE were extracted from the database of the National Programme on Substance Abuse Deaths, which receives information on drug-related deaths from Coroners in the UK and Islands (Isle of Man, Jersey, Guernsey) and other data suppliers. RESULTS: Eight cases, received by 3 September 2013, in which MXE was found at post-mortem and/or directly implicated in the death and/or mentioned in the Coroner's verdict are described. The median age at death was 27 years, with the majority of White ethnicity (6/8) and male (7/8). MXE was used together with other substances in 7/8 cases. MXE was found at post-mortem in all cases, directly implicated in the deaths of four and likely to have had an influence in two. CONCLUSIONS: More research needs to be conducted into its health effects and toxicity potential. Health care professionals should be made aware of the potential health harms of MXE, in order to develop early intervention measures and minimise the number of MXE-related poisonings and fatalities.

Venlafaxine as the 'baby ecstasy'? Literature overview and analysis of web-based misusers' experiences.

INTRODUCTION: Venlafaxine is one of the most frequently prescribed antidepressants worldwide, despite its toxicity risk in overdose. Furthermore, the molecule has been recently identified at the EU-wide level as one of the novel psychoactive substances. This paper aims at investigating the potential of misuse, taking into account both the existing literature and the analysis of the misusers' experiences as described in venlafaxine misuse web reports. METHODS: A literature search was performed using PubMed, Embase, and Medline. Posts/threads relating to venlafaxine misuse issues were identified through Google® and Yahoo® English-language searches. Resulting websites' data were then qualitatively assessed, and information was collected on a range of issues, including dosage, drug intake modalities, untoward drug effects, and association with other recreational drugs. RESULTS: A few literature case reports focusing on venlafaxine as a misusing drug were here identified. The molecule was here typically ingested or snorted at dosages up to 10-15 times higher than those clinically advised, obtaining MDMA/amphetamine-like stimulant and psychedelic effects. Polydrug misuse was commonly reported. Venlafaxine appeared to be widely available online for sale. CONCLUSIONS: Physicians should carefully evaluate patients for history of drug dependence and observe them for signs of venlafaxine misuse.

Benzodiazepine Boom: Tracking Etizolam, Pyrazolam, and Flubromazepam from Pre-UK Psychoactive Act 2016 to Present Using Analytical and Social Listening Techniques.

INTRODUCTION: The designer benzodiazepine (DBZD) market continues to expand whilst evading regulatory controls. The widespread adoption of social media by pro-drug use communities encourages positive discussions around DBZD use/misuse, driving demand. This research addresses the evolution of three popular DBZDs, etizolam (E), flubromazepam (F), and pyrazolam (P), available on the drug market for over a decade, comparing the quantitative chemical analyses of tablet samples, purchased from the internet prior to the implementation of the Psychoactive Substances Act UK 2016, with the thematic netnographic analyses of social media content. METHOD: Drug samples were purchased from the internet in early 2016. The characterisation of all drug batches were performed using UHPLC-MS and supported with 1H NMR. In addition, netnographic studies across the platforms X (formerly Twitter) and Reddit, between 2016-2023, were conducted. The latter was supported by both manual and artificial intelligence (AI)-driven thematic analyses, using numerous.ai and ChatGPT, of social media threads and discussions. RESULTS: UHPLC-MS confirmed the expected drug in every sample, showing remarkable inter/intra batch variability across all batches (E = 13.8 ± 0.6 to 24.7 ± 0.9 mg; F = 4.0 ± 0.2 to 23.5 ± 0.8 mg; P = 5.2 ± 0.2 to 11.5 ± 0.4 mg). 1H NMR could not confirm etizolam as a lone compound in any etizolam batch. Thematic analyses showed etizolam dominated social media discussions (59% of all posts), with 24.2% of posts involving sale/purchase and 17.8% detailing new administration trends/poly-drug use scenarios. Artificial intelligence confirmed three of the top five trends identified manually. CONCLUSIONS: Purity variability identified across all tested samples emphasises the increased potential health risks associated with DBZD consumption. We propose the global DBZD market is exacerbated by surface web social media discussions, recorded across X and Reddit. Despite the appearance of newer analogues, these three DBZDs remain prevalent and popularised. Reporting themes on harm/effects and new developments in poly-drug use trends, demand for DBZDs continues to grow, despite their potent nature and potential risk to life. It is proposed that greater controls and constant live monitoring of social media user content is warranted to drive active regulation strategies and targeted, effective, harm reduction strategies.

MDAI (5,6-methylenedioxy-2-aminoindane; 6,7-dihydro-5H-cyclopenta[f][1,3]benzodioxol-6-amine; 'sparkle'; 'mindy') toxicity: a brief overview and update.

OBJECTIVES: MDAI (5,6-methylenedioxy-2-aminoindane; 6,7-dihydro-5H-cyclopenta[f][1,3]benzodioxol-6-amine; 'sparkle'; 'mindy') is a psychoactive substance, sold primarily over the Internet and in 'head' shops as a 'legal high'. Synthesised and used as a research chemical in the 1990s, MDAI has structural similarities to MDMA (3,4-methylenedioxy-N-methylamphetamine) and shares its behavioural properties. Recreational use of MDAI appears to have started in Europe around 2007, with a noticeable increase after 2009 in the UK and other countries. Calls to National Poisons Information Services started in 2010, although there were few presentations to emergency departments by patients complaining of undesirable physical and psychiatric effects after taking MDAI. Recreational use of this drug has been reported only occasionally by online user fora. There is little scientifically based literature on the pharmacological, physiological, psychopharmacological, toxicological and epidemiological characteristics of this drug. METHODS: Recent literature (including 'grey') was searched to update what is known about MDAI, especially on its toxicity. RESULTS: The resultant information is presented, including on the first three UK deaths involving MDAI use in 2011 and 2012. 'Serotonin syndrome' appears to be a possible factor in these fatalities. CONCLUSION: It is vital that any other cases, including non-fatal overdoses, are documented so that a scientific evidence base can be established for them.

Cocaine-related health emergencies in Europe: a review of sources of information, trends and implications for service development.

BACKGROUND: Cocaine-related health consequences are difficult to observe. Data on drug users in health-emergency settings may be a useful source of information on consequences that are not visible via other information sources. METHODS: Thirty European countries submit an annual national report on the drug situation to the EMCDDA. All reports for the period 2007-2010 were analyzed, with particular attention given to auditing cocaine-related mentions. Analysis was also performed in order to identify sources and case definitions, assess coverage, audit cases and, where possible, to identify long-term trends. RESULTS: Considerable heterogeneity existed between countries in their approach to recording drug-related emergencies, with only Spain and the Netherlands having established formal indicators. The highest annual numbers of cocaine-related episodes were reported by the UK (3,502), Spain (2,845) and the Netherlands (1,211). A considerable (2- to 3-fold) increase in the numbers of cocaine-related episodes has been reported since the end of the 1990s in these countries; these increases peaked in Spain and England around 2007/08. CONCLUSIONS: The analysis reported here suggests the need to develop more standardized approaches to monitoring drug-related emergencies. It points to the potential value of developing effective referral links between the emergency and specialized drug services working with cocaine users.

Knowledge and Use of Over-the-counter Drugs in Italy: An Exploratory Survey-based Study in the General Population.

BACKGROUND: During the past decade, the misuse of over-the-counter (OTC) medicines has become a global public health concern, especially among young people. In this study, we aimed to explore the OTC consumption and related misuse in Italy and identify the demographic characteristics of people/individuals involved in this phenomenon, understanding eventual risk factors. METHODS: The study consisted of an anonymous online survey distributed by direct contact and via the Internet between June-November 2021 to the general population living in Italy. Descriptive statistics were reported, and binary regression analyses were performed to identify risk factors for lifetime misuse of OTC. The University of Hertfordshire approved the study (aLMS/SF/UH/02951). RESULTS: The final sample size was composed of 717 respondents. The sample was mainly represented by female (69.3%) students (39.9%) in the 20-25 years age group (30.0%). Based on the survey responses, study participants were divided into two groups according to the presence/absence of OTC abuse/misuse (127 versus 590), which were compared for possible predictors of OTC diversion. Multivariate regression showed that OTC abuse/misuse was associated with the knowledge of the effects of OTC [odds ratio/OR = 2.711, 95%Confidence Interval/CI 1.794-4.097, p <0.001]. On the contrary, the educational level appeared to be a protective factor [OR = 0.695, 95%CI 0.58-0.94, p = 0.016]. CONCLUSION: Although, according to our data, the phenomenon of OTC abuse appeared to be limited, increasing attention is needed because of possible underestimation and high-risk outcomes. Preventive strategies, including simplified access to information, may play a key role in limiting OTC misuse.

Ibogaine/Noribogaine in the Treatment of Substance Use Disorders: A Systematic Review of the Current Literature.

BACKGROUND: Ibogaine and noribogaine are psychedelic substances with dissociative properties naturally occurring in plants of the Apocynaceae family. Research has shown their efficacy in treating substance use disorders (SUD), particularly in opiate detoxification, but their efficacy and toxicity are still unclear. OBJECTIVE: This review aims to assess the anti-addictive role of ibogaine and evaluate its side effects. METHODS: A systematic literature review was conducted on the 29th of November 2021 using PubMed, Scopus and Web of Science databases through the following search strategy: ("Ibogaine" OR "Noribogaine") AND ("SUD" OR "substance use disorder" OR "craving" OR "abstinence" OR "withdrawal" OR "addiction" OR "detoxification") NOT animal NOT review NOT "vitro." The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed for data gathering purposes. Research methods were registered on PROSPERO (CRD42021287034). RESULTS: Thirty-one articles were selected for the systematic revision, and two were considered for analysis. The results were organised according to the type of study: case reports/case series, randomised- controlled trials (RCTs), open-label, survey and observational studies. The main outcomes were related to the anti-addictive effect of ibogaine and its cardiac toxicity. A meta-analysis of side effects was conducted using RevMan 5.4 software, showing a significant risk of developing headaches after ibogaine/noribogaine treatment. CONCLUSION: The results show some efficacy of ibogaine in the treatment of SUDs, but its cardiotoxicity and mortality are worrying. Further studies are needed to assess its therapeutic efficacy and actual safety.

5,6-Methylenedioxy-2-aminoindane: from laboratory curiosity to 'legal high'.

OBJECTIVES: The fully synthetic 'legal high' 5,6-methylenedioxy-2-aminoindane (MDAI) is an analogue of 3,4-methylenedioxymethamphetamine. Although developed in the 1990s, it was not widely abused until 2010. However, mephedrone was banned in the UK in April 2010, and almost immediately, MDAI was widely advertised as a legal alternative. This paper provides both an overview of the current state of knowledge of MDAI and a critical analysis of online available information relating to its psychoactive effects, adverse reactions and use in combination with other drugs. METHODS: The literature on MDAI was searched in three databases: PsycInfo, PubMed and MedScape. Once the availability of information on MDAI was identified within these websites, further specific searches were carried out for narratives focusing on the nature of its effects on users, motivations behind its recreational use and possible trends of misuse, and any other relevant information. RESULTS: Internet-sourced products have been shown variously to contain mephedrone, and mixed compositions of inorganic substances, while containing no MDAI. Numbers of Internet searches have been considerably higher in the UK compared with Germany and the US. CONCLUSIONS: Better international collaboration levels may be needed to tackle the novel and fast growing phenomenon of novel psychoactive drug availability from the web.

Pharmacovigilance Signals of the Opioid Epidemic over 10 Years: Data Mining Methods in the Analysis of Pharmacovigilance Datasets Collecting Adverse Drug Reactions (ADRs) Reported to EudraVigilance (EV) and the FDA Adverse Event Reporting System (FAERS).

In the past twenty years, the consumption of opioid medications has reached significant proportions, leading to a rise in drug misuse and abuse and increased opioid dependence and related fatalities. Thus, the purpose of this study was to determine whether there are pharmacovigilance signals of abuse, misuse, and dependence and their nature for the following prescription opioids: codeine, dihydrocodeine, fentanyl, oxycodone, pentazocine, and tramadol. Both the pharmacovigilance datasets EudraVigilance (EV) and the FDA Adverse Events Reporting System (FAERS) were analyzed to identify and describe possible misuse-/abuse-/dependence-related issues. A descriptive analysis of the selected Adverse Drug Reactions (ADRs) was performed, and pharmacovigilance signal measures (i.e., reporting odds ratio, proportional reporting ratio, information component, and empirical Bayesian geometric mean) were computed for preferred terms (PTs) of abuse, misuse, dependence, and withdrawal, as well as PTs eventually related to them (e.g., aggression). From 2003 to 2018, there was an increase in ADR reports for the selected opioids in both datasets. Overall, 16,506 and 130,293 individual ADRs for the selected opioids were submitted to EV and FAERS, respectively. Compared with other opioids, abuse concerns were mostly recorded in relation to fentanyl and oxycodone, while tramadol and oxycodone were more strongly associated with drug dependence and withdrawal. Benzodiazepines, antidepressants, other opioids, antihistamines, recreational drugs (e.g., cocaine and alcohol), and several new psychoactive substances, including mitragynine and cathinones, were the most commonly reported concomitant drugs. ADRs reports in pharmacovigilance databases confirmed the availability of data on the abuse and dependence of prescription opioids and should be considered a resource for monitoring and preventing such issues. Psychiatrists and clinicians prescribing opioids should be aware of their misuse and dependence liability and effects that may accompany their use, especially together with concomitant drugs.

Hearing impairment in children living with HIV in Haiti.

OBJECTIVE: To identify the prevalence of hearing impairment and associated risk factors in children living with human immunodeficiency virus (HIV) in Haiti. METHODS: A validated smartphone-based platform with pure-tone audiometry was used to screen 341 HIV-infected children for hearing impairment in Port-au-Prince, Haiti from March 2019 to September 2020. If screening was failed, a more comprehensive pure-tone audiometric evaluation was administered. Demographic, otologic, and HIV-related data were obtained through caregiver surveys and medical charts. Statistical analysis included univariate and multivariate logistic regression. RESULTS: Sixty (18%) of 341 HIV-infected children (ages 7-18 years) had hearing impairment. Of those failing their hearing assessment, 17 (28%) had moderate and 5 (8%) had severe or profound hearing loss. Hearing impairment was associated with frequent ear infections (OR 3.37; 95% CI 1.76-6.46; p < 0.001) and family history of hearing loss (OR 5.12; 95% CI 2.14-12.23; p = 0.001) but not viral load (OR 1.00; 95% CI 0.73-1.02; p = 0.28) or antiretroviral therapy duration (OR 0.96; 95% CI 0.79-1.17; p = 0.66). Only 35% of caregivers correctly perceived their child's hearing loss. CONCLUSIONS: Hearing impairment occurs at a higher prevalence in HIV-infected children in Haiti than what is expected for those living without HIV. Frequent ear infections were significantly associated with hearing loss while antiretroviral therapy duration was not. Despite their potential ototoxicity, antiretroviral therapies should be continued and may decrease incidence of otitis media. Low caregiver perception of hearing loss emphasizes the need for routine hearing screening for HIV-infected children.

Deaths of opiate/opioid misusers involving dihydrocodeine, UK, 1997-2007.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Dihydrocodeine (DHC) is an opioid analgesic sometimes prescribed as an alternative to other medications (e.g. methadone and buprenorphine) for opioid misuse. Its effectiveness is, however, still controversial. DHC prescription rates seem to be related to levels of DHC fatalities, possibly in relation to levels of disregard of the availability of supervised or interval dispensing of opioids, but no large-scale analysis of DHC fatalities has been carried out. We analysed here involvement of DHC in fatalities that occurred between 1997 and 2007 among individuals with a history of opiate/opioid misuse reported to the National Programme on Substance Abuse Deaths (np-SAD). WHAT THIS STUDY ADDS: DHC, either alone or in combination, was identified in 584 fatalities. Typical cases identified were males in their early thirties. In accidental overdoses, DHC, which had been prescribed to 45% of the victims, was typically identified in combination with other drugs, such as heroin/morphine, methadone and hypnotics/sedatives. Both paracetamol and antidepressants were more typically identified in combination with DHC in suicides. Opiate/opioid misusers should be educated about risks associated with polydrug intake and prescribers should carefully consider a pharmacological intervention alternative to DHC (e.g. methadone, buprenorphine) when managing and treating opiate addiction. AIMS: Although its effectiveness is somewhat controversial, it appears that dihydrocodeine (DHC) is still prescribed in the UK as an alternative to both methadone and buprenorphine for the treatment of opiate addiction. METHODS: Data covering the period 1997-2007 voluntarily supplied by coroners were analysed. All cases pertaining to victims with a clear history of opiate/opioid misuse and in which DHC, either on its own or in combination, was identified at post-mortem toxicology and/or implicated in death, were extracted from the database. RESULTS: Dihydrocodeine, either alone or in combination, was identified in 584 fatalities meeting the selection criteria. In 44% of cases it was directly implicated in the cause of death. These cases represented about 6.8% of all opiate/opioid-related deaths during this period. Typical DHC cases identified were White males in their early thirties. Accidental deaths (96%) were likely to involve DHC in combination with other psychoactives, mainly heroin/morphine, hypnotics/sedatives and methadone. Both paracetamol and antidepressants were found in proportionately more suicide cases than in accidental overdoses. DHC had been prescribed to the decedent in at least 45% of cases. CONCLUSIONS: Opiate/opioid misusers should be educated about risks associated with polydrug intake. More in particular, co-administration of DHC with heroin, methadone and benzodiazepines may increase the risk of accidental fatal overdose. Prescribers should carefully consider pharmacological intervention alternative to DHC (e.g. methadone, buprenorphine) when managing and treating opiate addiction. More resources are required to do prospective research in this area.

The e-psychonaut drugs' psychopharmacology.

The focus here was on the pharmacological and clinical pharmacological issues pertaining to the vast range of drugs (e.g. synthetic cannabimimetics, synthetic opioids, novel stimulants, novel psychedelics, PCP/ketamine-like compounds, prescribed medicinal compounds and popular psychotropic herbs/plants) discussed by Internet-based enthusiasts of new/novel psychoactive substances (NPS), 'e-psychonauts'. Currently ongoing related in silico studies, followed by further in vitro and in vivo/preclinical studies, will hopefully provide important findings in terms of which molecules within each given NPS class may present with higher levels of receptor affinities, and hence clinical potency. Understanding the pharmacological characteristics/potency of those novel recreational molecules will hopefully help in predicting related NPS diffusion, morbidity and possible lethality data.

Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant.

Kratom or Mitragyna speciosa (Korth.) is an evergreen tree of the coffee family native to South-East Asia and Australasia. It is used by locals recreationally to induce stimulant and sedative effects and medically to soothe pain and opiate withdrawal. Its leaves are smoked, chewed, or infused, or ground to yield powders or extracts for use as liquids. It contains more than 40 alkaloids; among these, mitragynine and 7-hydroxymitragynine are endowed with variable mu, delta, and kappa opioid stimulating properties (with 7-hydroxymitragynine having a more balanced affinity), rhynchophylline, which is a non-competitive NMDA glutamate receptor antagonist, but is present in negligible quantities, and raubasine, which inhibits α1-adrenceptors preferentially over α2-adrenceptors, while the latter are bound by 7-hydroxymitragynine, while mitragynine counters 5-HT2A receptors. This complexity of neurochemical mechanisms may account for kratom's sedative-analgesic and stimulant effects. It is commonly held that kratom at low doses is stimulant and at higher doses sedative, but no cut-off has been possible to define. Long-term use of kratom may produce physical and psychological effects that are very similar to its withdrawal syndrome, that is, anxiety, irritability, mood, eating, and sleep disorders, other than physical symptoms resembling opiate withdrawal. Kratom's regulatory status varies across countries; in Italy, both mitragynine and the entire tree and its parts are included among regulated substances. We describe the case of a patient who developed anxiety and dysphoric mood and insomnia while using kratom, with these symptoms persisting after withdrawal. He did not respond to a variety of antidepressant combinations and tramadol for various months, and responded after 1 month of clomipramine. Well-being persisted after discontinuing tramadol.

Focus on Over-the-Counter Drugs' Misuse: A Systematic Review on Antihistamines, Cough Medicines, and Decongestants.

Background: Over the past 20 years or so, the drug misuse scenario has seen the emergence of both prescription-only and over-the-counter (OTC) medications being reported as ingested for recreational purposes. OTC drugs such as antihistamines, cough/cold medications, and decongestants are reportedly the most popular in being diverted and misused. Objective: While the current related knowledge is limited, the aim here was to examine the published clinical data on OTC misuse, focusing on antihistamines (e.g., diphenhydramine, promethazine, chlorpheniramine, and dimenhydrinate), dextromethorphan (DXM)- and codeine-based cough medicines, and the nasal decongestant pseudoephedrine. Methods: A systematic literature review was carried out with the help of Scopus, Web of Science databases, and the related gray literature. For data gathering purposes, both the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and PROSPERO guidelines were followed (PROSPERO identification code CRD42020209261). Results: After completion of the selection, eligibility, and screening phases, some 92 articles were here taken into consideration; case reports, surveys, and retrospective case series analyses were included. Findings were organized according to the specific OTC recorded. Most articles focused here on DXM (n = 54) and diphenhydramine (n = 12). When specified, dosages, route(s) of administration, toxicity symptoms (including both physical and psychiatric ones), and outcomes were here reported. Conclusion: Results from the systematic review showed that the OTC misusing issues are both widespread worldwide and popular; vulnerable categories include adolescents and young adults, although real prevalence figures remain unknown, due to a lack of appropriate monitoring systems. Considering the potential, and at times serious, adverse effects associated with OTC misusing issues, healthcare professionals should be vigilant, and ad hoc preventative actions should be designed and implemented.

An index of fatal toxicity for drugs of misuse.

OBJECTIVE: To determine the lethal toxicity of five commonly-used illicit substances by relating the number of associated deaths to their availability. METHODS: An index of toxicity was calculated for each of five drugs [heroin, cocaine/crack, ecstasy (MDMA), amphetamine and cannabis] as the ratio of the number of deaths associated with that substance to its availability in the period 2003-2007. Three separate proxy measures of availability were used (number of users as determined by household surveys, number of seizures by law enforcement agencies and estimates of the market size). All data are related to England and Wales only. RESULTS: There was a broad correlation between all three denominators of availability. Not unexpectedly, heroin and cannabis showed, respectively, the highest and lowest toxicities. The index of fatal toxicity of MDMA was close to that of amphetamine and cocaine/crack. There was a rank correlation between this index and other measures of lethal toxicity based on safety ratios. CONCLUSIONS: These results are contrary to widely-held public views of the relative fatal toxicity of MDMA.

'New/Designer Benzodiazepines': An Analysis of the Literature and Psychonauts' Trip Reports.

BACKGROUND: NPS belonging to the benzodiazepine (BZD) class, e.g., 'legal/designer BZDs'/'research chemicals', have recently emerged in the drug (mainly online/virtual) market. OBJECTIVE: While certain NPS belonging to the BZD class possess pharmacological profiles similar to controlled pharmaceutical BZDs, clinical and pharmacological profiles of current emerging BZDs are still not well-described. Therefore, there is a need to increase clinicians'/public health knowledge/awareness, to incentive harm reduction strategies. METHOD: A comprehensive overview was carried out by using the EMCDDA/EDND database regularly monitored by our research team, by specifically looking at the 'new BZDs' so far notified. Furthermore, given the limitation of peer-reviewed data published so far, a nonparticipant multilingual qualitative netnographic study was conducted to obtain further clinical/pharmacological/ toxicological data, including psychonauts' online trip reports. RESULTS: First designer BZDs appeared as NPS around 2007. So far, 29 designer BZDs have been notified to the EMCDDA, being some of them extremely powerful, also at lower dosages. They are sold as tablets/powder/pellets/capsules/blotters/liquids, at very affordable prices, and variably administered. Some are also sold on the illicit drugmarket as counterfeit forms of traditional BZDs or as either adulterants or diluents in heroin or other synthetic opioids/cannabinoids. Nowadays, there is no guarantee of the quality of designer BZDs composition/purification and, hence, most NPS consumers may be inadvertently exposed to unsafe and harmful compounds. CONCLUSION: Given the limited information on their pharmacology/toxicity, variations in dosage, onset of effects, combination of substances, potency, and general patient or individual variability, the concomitant use of these substances with other drugs entails several and unpredictable risks.