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BackgroundMethylphenidate (MPH), a central nervous system stimulant primarily prescribed for attention-deficit/hyperactivity disorder (ADHD), has seen increasing rates of misuse and abuse, particularly in patients with dual diagnosis (co-occurring psychiatric disorders and substance use disorders/SUDs). The heightened risk of dependence and adverse effects in these vulnerable populations warrants a systematic review to assess the prevalence and pattern of abuse/misuse of MPH among patients within this population and to understand potential risk factors, patterns of misuse, and outcomes, including the impact on psychiatric symptoms and overall mental health, the effects on SUD (e.g., exacerbation or mitigation of symptoms), and the incidence of adverse events and complications (e.g., cardiovascular issues, psychological effects).MethodologyA systematic review was conducted in August-September 2024 using both PubMed and Scopus databases. The following search strategy was used: TITLE-ABS-KEY (methylphenidate OR Ritalin OR Concerta) AND TITLE-ABS-KEY (abuse OR misuse OR dependency OR addiction) AND TITLE-ABS-KEY (dual diagnosis OR comorbid psychiatric disorder OR psychiatric disorder AND substance use disorder). The systematic review was structured in accordance with the PRISMA guidelines and identified studies were assessed by title/abstract and full text screening against eligibility criteria.ResultsA total of 12 studies were selected for analysis after screening for relevance, quality, and adherence to inclusion criteria. Findings indicated that individuals with psychiatric disorders, particularly conduct disorder (N=593/1551 individuals), mood disorder (N=90/1551 individuals), anxiety disorder (N=66/1551 individuals), personality disorder (N=44/1551 individuals) and major depression disorder (N=40/1551 individuals), were more likely to misuse MPH. Co-occurring SUD, especially involving Alcohol Use Disorder (N=475/1551 individuals), Cannabis Use Disorder (N=371/1551 individuals), Nicotine Use Disorder (N=343/1551 individuals), Cocaine Use Disorder (N=68/1551 individuals), significantly elevated the risk. Misuse often involved higher doses than prescribed (N=84/1551 individuals) or using non-oral routes of administration (N=20/1551 individuals; e.g., snorting). Adverse outcomes included heightened risk of gastrointestinal events (N=201/1551 individuals), cardiovascular events (N=108/1551 individuals), psychosis (N=69/1551 individuals), and exacerbation of psychiatric symptoms (N=1082/1551 individuals).ConclusionMPH misuse and abuse are significant concerns in patients with psychiatric disorders and SUD. Risk factors include impulsivity, history of substance abuse, and access to prescription stimulants. Integrated therapeutic approaches and stricter prescription monitoring are recommended to mitigate misuse risks.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024576724.

Glucagon-like peptide-1 (GLP-1) is involved in a range of central and peripheral pathways related to appetitive behavior. Hence, this study explored the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on substance and behavioral addictions, including alcohol, caffeine, nicotine, cannabis, psychostimulants, compulsive shopping, and sex drive/libido. Data were collected from various social platforms. Keywords related to GLP-1 RAs and substance/behavioral addiction were used to extract relevant comments. The study employed a mixed-methods approach to analyze online discussions posted from December 2019 to June 2023 and collected using a specialized web application. Reddit entries were the focus here due to limited data from other platforms, such as TikTok and YouTube. A total of 5859 threads and related comments were extracted from six subreddits, which included threads about GLP-1 RAs drugs and associated brand names. To obtain relevant posts, keywords related to potential substance use and compulsive behavior were selected. Further analysis involved two main steps: (1) manually coding posts based on users’ references to the potential impact of GLP-1 RAs on substance use and non-substance habits, excluding irrelevant or unclear comments; (2) performing a thematic analysis on the dataset of keywords, using AI-assisted techniques followed by the manual revision of the generated themes. Second, a thematic analysis was performed on the keyword-related dataset, using AI-assisted techniques followed by the manual revision of the generated themes. In total, 29.75% of alcohol-related; 22.22% of caffeine-related; and 23.08% of nicotine-related comments clearly stated a cessation of the intake of these substances following the start of GLP-1 RAs prescription. Conversely, mixed results were found for cannabis intake, and only limited, anecdotal data were made available for cocaine, entactogens, and dissociative drugs’ misuse. Regarding behavioral addictions, 21.35% of comments reported a compulsive shopping interruption, whilst the sexual drive/libido elements reportedly increased in several users. The current mixed-methods approach appeared to be a useful tool in gaining insight into complex topics such as the effects of GLP-1 RAs on substance and non-substance addiction-related disorders; some GLP-1 RA-related mental health benefits could also be inferred from here. Overall, it appeared that GLP-1 RAs may show the potential to target both substance craving and maladaptive/addictive behaviors, although further empirical research is needed.

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has gained considerable attention as a therapeutic agent for type 2 diabetes mellitus and obesity. Despite its clinical success, the precise mechanisms underlying its pharmacological effects remain incompletely understood. In this study, we employed ligand-based drug design strategies to investigate potential off-target interactions of semaglutide. Through a comprehensive in silico screening of semaglutide’s structural properties against a diverse panel of proteins, we have identified calmodulin (CaM) as a putative novel target of semaglutide. Molecular docking simulations revealed a strong interaction between semaglutide and CaM, characterized by favourable binding energies and a stable binding pose. Further molecular dynamics simulations confirmed the stability of the semaglutide–CaM complex, emphasizing the potential for a physiologically relevant interaction. In conclusion, our ligand-based drug design approach has uncovered calmodulin as a potential novel target of semaglutide. This discovery sheds light on the complex pharmacological profile of semaglutide and offers a promising direction for further research into the development of innovative therapeutic strategies for metabolic disorders. The CaM, and especially so the CaMKII, system is central in the experience of both drug- and natural-related reward. It is here hypothesized that, due to semaglutide binding, the reward pathway-based calmodulin system may be activated, and/or differently regulated. This may result in the positive semaglutide action on appetitive behaviour. Further studies are required to confirm these findings.

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.

The emergence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs; semaglutide and others) now promises effective, non-invasive treatment of obesity for individuals with and without diabetes. Social media platforms’ users started promoting semaglutide/Ozempic as a weight-loss treatment, and the associated increase in demand has contributed to an ongoing worldwide shortage of the drug associated with levels of non-prescribed semaglutide intake. Furthermore, recent reports emphasized some GLP-1 RA-associated risks of triggering depression and suicidal thoughts. Consistent with the above, we aimed to assess the possible impact of GLP-1 RAs on mental health as being perceived and discussed in popular open platforms with the help of a mixed-methods approach. Reddit posts yielded 12,136 comments, YouTube videos 14,515, and TikTok videos 17,059, respectively. Out of these posts/entries, most represented matches related to sleep-related issues, including insomnia (n = 620 matches); anxiety (n = 353); depression (n = 204); and mental health issues in general (n = 165). After the initiation of GLP-1 RAs, losing weight was associated with either a marked improvement or, in some cases, a deterioration, in mood; increase/decrease in anxiety/insomnia; and better control of a range of addictive behaviors. The challenges of accessing these medications were a hot topic as well. To the best of our knowledge, this is the first study documenting if and how GLP-1 RAs are perceived as affecting mood, mental health, and behaviors. Establishing a clear cause-and-effect link between metabolic diseases, depression and medications is difficult because of their possible reciprocal relationship, shared underlying mechanisms and individual differences. Further research is needed to better understand the safety profile of these molecules and their putative impact on behavioral and non-behavioral addictions.

Recent media reports commented about a possible issue of the misuse of antidiabetics related to molecules promoted as a weight-loss treatment in non-obese people. We evaluated here available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and tirzepatide) and the phentermine–topiramate combination. To acheieve that aim, we analyzed the Food and Drug Administration’s FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AERs) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018–December 2022, a total of 31,542 AERs involving the selected molecules were submitted to FAERS; most involved dulaglutide (n = 11,858; 37.6%) and semaglutide (n = 8249; 26.1%). In comparing semaglutide vs. the remaining molecules, the respective PRR values of the AERs ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’, and ‘intentional product use issue’ were 4.05, 4.05, 3.60, and 1.80 (all < 0.01). The same comparisons of semaglutide vs. the phentermine–topiramate combination were not associated with any significant differences. To the best of our knowledge, this is the first study documenting the misuse/abuse potential of semaglutide in comparison with other GLP1 analogues and the phentermine–topiramate combination. The current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Background Cognitive enhancers (CE) are often used to improve memory, alertness and cognitive capacity. These products are commercially and pharmaceutically available. Due to high academic pressure, university students are at risk of CE misuse. However, data regarding this issue are limited, especially in the United Arab Emirates (UAE). Aims To assess the prevalence of CE intake; evaluate students’ knowledge of these substances; and identify student characteristics associated with CE usage. Method A cross sectional study based on a validated online survey that was distributed using university-licensed software (Qualtrics) as a direct web link via email and social media to all Medical, Pharmacy, Dentistry, Nursing and Engineering students enrolled in six UAE universities. Associations between student characteristics and CE use were investigated using the chi-squared test and multiple logistic regression. Reasons for CE use, temporal patterns of use, details regarding purchase and types of CE used were compared by gender. Results One quarter of students had used CEs. There was a clear difference between users and non-users in terms of gender (pConclusions Universities need to address the prevalence of CE use amongst their students by providing effective support programs.

Background and Aims: COVID-19 has infected more than 77 million people worldwide and impacted the lives of many more, with a particularly devastating impact on vulnerable populations, including people with substance use disorders (SUDs). Quarantines, travel bans, regulatory changes, social distancing, and “lockdown” measures have affected drug and alcohol supply chains and subsequently their availability, price, and use patterns, with possible downstream effects on presentations of SUDs and demand for treatment. Given the lack of multicentric epidemiologic studies, we conducted a rapid global survey within the International Society of Addiction Medicine (ISAM) network in order to understand the status of substance-use patterns during the current pandemic.Design: Cross-sectional survey.Setting: Worldwide.Participants: Starting on April 4, 2020 during a 5-week period, the survey received 185 responses from 77 countries.Measurements: To assess addiction medicine professionals' perceived changes in drug and alcohol supply, price, use pattern, and related complications during the COVID-19 pandemic.Findings: Participants reported (among who answered “decreased” or “increased”) a decrease in drug supply (69.0%) and at the same time an increase in price (95.3%) globally. With respect to changes in use patterns, an increase in alcohol (71.7%), cannabis (63.0%), prescription opioids (70.9%), and sedative/hypnotics (84.6%) use was reported, while the use of amphetamines (59.7%), cocaine (67.5%), and opiates (58.2%) was reported to decrease overall.Conclusions: The global report on changes in the availability, use patterns, and complications of alcohol and drugs during the COVID-19 pandemic should be considered in making new policies and in developing mitigating measures and guidelines during the current pandemic (and probable future ones) in order to minimize risks to people with SUD.

The interpretation of post-mortem human tissue toxicology levels may be affected by the sampling site chosen. It is important to bear this in mind when looking at the psychoactive constituents of khat (Catha edulis Forsk) that have been consumed and have contributed to or caused death.The post-mortem levels of cathine, cathinone and norephedrine/ norpseudoephedrine are very rarely reported, thereby making it impossible for toxicologists, pathologists and others investigating khat-related fatalities to decide if a level is toxic or fatal. This paper presents all the published data that exists to help start documenting this neglected area. Such information should be collected and reported on a systematic basis to facilitate correct interpretations in the future.

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.

Background: The coronavirus disease 2019 (COVID-19) pandemic has impacted people with substance use disorders (SUDs) worldwide, and healthcare systems have reorganized their services in response to the pandemic.Methods: One week after the announcement of the COVID-19 as a pandemic, in a global survey, 177 addiction medicine professionals described COVID-19-related health responses in their own 77 countries in terms of SUD treatment and harm reduction services. The health responses were categorized around (1) managerial measures and systems, (2) logistics, (3) service providers, and (4) vulnerable groups.Results: Respondents from over 88% of countries reported that core medical and psychiatric care for SUDs had continued; however, only 56% of countries reported having had any business continuity plan, and 37.5% of countries reported shortages of methadone or buprenorphine supplies. Participants of 41% of countries reported partial discontinuation of harm-reduction services such as needle and syringe programs and condom distribution. Fifty-seven percent of overdose prevention interventions and 81% of outreach services were also negatively impacted.Conclusions: Participants reported that SUD treatment and harm-reduction services had been significantly impacted globally early during the COVID-19 pandemic. Based on our findings, we highlight several issues and complications resulting from the pandemic concerning people with SUDs that should be tackled more efficiently during the future waves or similar pandemics. The issues and potential strategies comprise the following: (1) helping policymakers to generate business continuity plans, (2) maintaining the use of evidence-based interventions for people with SUDs, (3) being prepared for adequate medication supplies, (4) integrating harm reduction programs with other treatment modalities, and (5) having specific considerations for vulnerable groups such as immigrants and refugees.

COVID-19-related disruptions of people and goods' circulation can affect drug markets, especially for new psychoactive substances (NPSs). Drug shortages could cause a change in available NPS, with the introduction of new, unknown, substances. The aims of the current research were to use a web crawler, NPSfinder®, to identify and categorize emerging NPS discussed on a range of drug enthusiasts/psychonauts' websites/fora at the time of the pandemic; social media for these identified NPS were screened as well. The NPSfinder® was used here to automatically scan 24/7 a list of psychonaut websites and NPS online resources. The NPSs identified in the time frame between January and August 2020 were searched in both the European Monitoring Center for Drugs and Drug Addictions (EMCDDA)/United Nations Office on Drugs and Crime (UNODC) databases and on social media (Facebook, Twitter, Instagram, Pinterest, and YouTube) as well, with a content qualitative analysis having been carried out on reddit.com. Of a total of 229 NPSs being discussed at the time of the pandemic, some 18 NPSs were identified for the first time by the NPSfinder®. These included six cathinones, six opioids, two synthetic cannabinoid receptor agonists (SCRAs), two phenylcyclohexylpiperidine (PCP)-like molecules, and two psychedelics. Of these NPSs, 10 were found to be previously unreported to either the UNODC or the EMCDDA. Of these 18 NPSs, opioids and cathinones were the most discussed on social media/reddit, with the highest number of threads associated. Current findings may support the use of both automated web crawlers and social listening approaches to identify emerging NPSs; the pandemic-related imposed restrictions may somehow influence the demand for specific NPS classes.

Despite increasing reports, antidepressant (AD) misuse and dependence remain underestimated issues, possibly due to limited epidemiological and pharmacovigilance evidence. Thus, here we aimed to determine available pharmacovigilance misuse/abuse/dependence/withdrawal signals relating to the Selective Serotonin Reuptake Inhibitors (SSRI) citalopram, escitalopram, paroxetine, fluoxetine, and sertraline. Both EudraVigilance (EV) and Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) datasets were analysed to identify AD misuse/abuse/dependence/withdrawal issues. A descriptive analysis was performed; moreover, pharmacovigilance measures, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the empirical Bayesian geometric mean (EBGM) were calculated. Both datasets showed increasing trends of yearly reporting and similar signals regarding abuse and dependence. From the EV, a total of 5335 individual ADR reports were analysed, of which 30% corresponded to paroxetine (n = 1592), 27% citalopram (n = 1419), 22% sertraline (n = 1149), 14% fluoxetine (n = 771), and 8% escitalopram (n = 404). From FAERS, a total of 144,395 individual ADR reports were analysed, of which 27% were related to paroxetine, 27% sertraline, 18% citalopram, 16% fluoxetine, and 13% escitalopram. Comparing SSRIs, the EV misuse/abuse-related ADRs were mostly recorded for citalopram, fluoxetine, and sertraline; conversely, dependence was mostly associated with paroxetine, and withdrawal to escitalopram. Similarly, in the FAERS dataset, dependence/withdrawal-related signals were more frequently reported for paroxetine. Although SSRIs are considered non-addictive pharmacological agents, a range of proper withdrawal symptoms can occur well after discontinuation, especially with paroxetine. Prescribers should be aware of the potential for dependence and withdrawal associated with SSRIs.

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.

BackgroundThere is growing availability of novel psychoactive substances (NPS), including cognitive enhancers (CEs) which can be used in the treatment of certain mental health disorders. While treating cognitive deficit symptoms in neuropsychiatric or neurodegenerative disorders using CEs might have significant benefits for patients, the increasing recreational use of these substances by healthy individuals raises many clinical, medico-legal, and ethical issues. Moreover, it has become very challenging for clinicians to keep up-to-date with CEs currently available as comprehensive official lists do not exist.MethodsUsing a web crawler (NPSfinder®), the present study aimed at assessing psychonaut fora/platforms to better understand the online situation regarding CEs. We compared NPSfinder® entries with those from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and from the United Nations Office on Drugs and Crime (UNODC) NPS databases up to spring 2019. Any substance that was identified by NPSfinder® was considered a CE if it was either described as having nootropic abilities by psychonauts or if it was listed among the known CEs by Froestl and colleagues.ResultsA total of 142 unique CEs were identified by NPSfinder®. They were divided into 10 categories, including plants/herbs/products (29%), prescribed drugs (17%), image and performance enhancing drugs (IPEDs) (15%), psychostimulants (15%), miscellaneous (8%), Phenethylamines (6%), GABAergic drugs (5%), cannabimimetic (4%), tryptamines derivatives (0.5%), and piperazine derivatives (0.5%). A total of 105 chemically different substances were uniquely identified by NPSfinder®. Only one CE was uniquely identified by the EMCDDA; no CE was uniquely identified by the UNODC.ConclusionsThese results show that NPSfinder® is helpful as part of an Early Warning System, which could update clinicians with the growing numbers and types of nootropics in the increasingly difficult-to-follow internet world. Improving clinicians’ knowledge of NPS could promote more effective prevention and harm reduction measures in clinical settings.

BackgroundA wide range of novel psychoactive substances (NPSs) are regularly searched and discussed online by e-psychonauts. Among NPSs, the range of prescription/non-prescription opioids (fentanyl and non-fentanyl analogs) and herbal derivatives currently represents a challenge for governments and clinicians.MethodsUsing a web crawler (i.e., NPS.Finder®), the present study aimed at assessing psychonaut fora/platforms to better understand the online situation regarding opioids.ResultsThe open-web crawling/navigating software identified some 426 opioids, including 234 fentanyl analogs. Of these, 176 substances (162 were very potent fentanyls, including two ohmefentanyl and seven carfentanyl analogs) were not listed in either international or European NPS databases.ConclusionA web crawling approach helped in identifying a large number, indeed higher than that listed by European/international agencies, of unknown opioids likely to possess a significant misuse potential. Most of these novel/emerging substances are still relatively unknown. This is a reason of concern; each of these analogs potentially presents with different toxicodynamic profiles, and there is a lack of docking, preclinical, and clinical observations. Strengthening multidisciplinary collaboration between clinicians and bioinformatics may prove useful in better assessing public health risks associated with opioids.

(1) Background: Over the last decade, misuse and diversion of medications has appeared to be increasingly concerning phenomena, including a range of different molecules. As current knowledge on the abuse of centrally acting anticholinergics is limited, the aim of the present study is to review the relevant published data, focusing on the following molecules: benztropine, biperiden, scopolamine, orphenadrine, and benzhexol/trihexyphenidyl (THP). (2) Methods: A systematic literature review was carried out using Pubmed, Scopus, and Web of Science databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Research methods were registered on PROSPERO (CRD42021257293). (3) Results: A total of 48 articles, including case reports, surveys, and retrospective case series analyses, were included. Most articles focused on benzhexol/THP (n = 25), and benztropine (n = 4). The routes of administration were mostly oral, and macrodoses together concomitant illicit drugs, e.g., cocaine, have been recorded. Toxidromes included both physical (e.g., tachycardia, tachypnoea, dilatated pupils, dry skin, urinary retention, ataxia, etc.) and psychiatric symptoms (e.g., anxiety, agitation, delirium, etc.). Fatal outcomes were very rare but reported. (4) Conclusion: Results from the present study show that anticholinergic misusing issues are both widespread worldwide and popular. Considering the potential adverse effects associated, healthcare professionals should be vigilant and monitor eventual misusing issues.

The restrictive measures adopted during the COVID-19 pandemic modified some previously consolidated drug use patterns. A focus on social networks allowed drug users to discuss, share opinions and provide advice during a worldwide emergency context. In order to explore COVID-19-related implications on drug trends/behaviour and on most popular psychotropic substances debated, the focus here was on the constantly updated, very popular, Reddit social platform’s posts and comments. A quantitative and qualitative analysis of r/Drugs and related subreddits, using a social media listening netnographic approach, was carried out. The post/comments analysed covered the time-frame December 2019–May 2020. Between December 2019 and May 2020, the number of whole r/Drugs subreddit members increased from 619,563 to 676,581 members, respectively, thus increasing by 9.2% by the end of the data collection. Both the top-level r/Drugs subreddit and 92 related subreddits were quantitatively analysed, with posts/comments related to 12 drug categories. The drugs most frequently commented on included cannabinoids, psychedelics, opiates/opioids, alcohol, stimulants and prescribed medications. The qualitative analysis was carried out focussing on four subreddits, relating to some 1685 posts and 3263 comments. Four main themes of discussion (e.g., lockdown-associated immunity and drug intake issues; drug-related behaviour/after-quarantine plans’ issues; lockdown-related psychopathological issues; and peer-to-peer advice at the time of COVID-19) and four categories of Redditors (e.g., those continuing the use of drugs despite the pandemic; the “couch epidemiologists”; the conspirationists/pseudo-science influencers; and the recovery-focused users) were tentatively identified here. A mixed-methods, social network-based analysis provided a range of valuable information on Redditors’ drug use/behaviour during the first phase of the COVID-19 pandemic. Further studies should be carried out focusing on other social networks as well as later phases of the pandemic.

Designer benzodiazepines (DBZDs) represent a serious health concern and are increasingly reported in polydrug consumption-related fatalities. When new DBZDs are identified, very limited information is available on their pharmacodynamics. Here, computational models (i.e., quantitative structure-activity relationship/QSAR and Molecular Docking) were used to analyse DBZDs identified online by an automated web crawler (NPSfinder®) and to predict their possible activity/affinity on the gamma-aminobutyric acid A receptors (GABA-ARs). The computational software MOE was used to calculate 2D QSAR models, perform docking studies on crystallised GABA-A receptors (6HUO, 6HUP) and generate pharmacophore queries from the docking conformational results. 101 DBZDs were identified online by NPSfinder®. The validated QSAR model predicted high biological activity values for 41% of these DBDZs. These predictions were supported by the docking studies (good binding affinity) and the pharmacophore modelling confirmed the importance of the presence and location of hydrophobic and polar functions identified by QSAR. This study confirms once again the importance of web-based analysis in the assessment of drug scenarios (DBZDs), and how computational models could be used to acquire fast and reliable information on biological activity for index novel DBZDs, as preliminary data for further investigations.

Background and Objectives: Over the past twenty years a large number of new psychoactive substances (NPS) have entered and modified the recreational drug scene. Their intake has been associated with health-related risks, especially so for vulnerable populations such as people with severe mental illness, who might be at higher risk of suicidality or self-injurious behavior. This paper aims at providing an overview of NPS abuse and the effects on mental health and suicidality issues, by performing a literature review of the current related knowledge, thereby identifying those substances that, more than others, are linked to suicidal behaviors. Materials and Methods: A comprehensive and updated overview of the literature regarding suicidality and NPS categories has been undertaken. An electronic search was performed, including all papers published up to March 2021, using the following keywords “NPS” OR “new psychoactive substances” OR “novel psychoactive substances” OR “synthetic cannabinoids” OR “phenethylamines” OR “synthetic cathinones” OR “tryptamines” OR “piperazines” OR “new synthetic opioids” OR “designer benzodiazepines” AND (“suicide” OR “suicidality”) NOT review NOT animal on the PubMed, Cochrane Library, and Web of Science online databases. Results: Suicidality and self-injurious behavior appear to be frequently associated with some NPS such as cathinones, synthetic cannabinoids, and new synthetic opioids. The results are organized according to the substances recorded. Conclusion: The growing use of NPS has become a significant clinical issue, causing increasing concern and challenges for clinicians working in both mental health and emergency departments. Thus, considering the associations between NPS and suicidality or self-injurious behaviors, areas where suicide-prevention efforts and strategies might be focused are the early detection, monitoring, and restriction of NPS.

Objective: A recent, global, increase in the use of opioids including the prescribing, highly potent, fentanyl has been recorded. Due its current popularity and the potential lethal consequences of its intake, we aimed here at analyzing the fentanyl misuse, abuse, dependence and withdrawal-related adverse drug reactions (ADRs) identified within the European Medicines Agency (EMA), the United Kingdom Yellow Card Scheme (YCS), and the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) databases.Methods: Descriptive analysis of both ADRs and related cases.Results: The analysis of fentanyl-related misuse, abuse, dependence and withdrawal cases reported during years 2004–2018 to the EMA, the YCS, and the FAERS showed increasing levels overtime, specifically, EMA-related data presented two peaks (e.g., in 2008 and 2015), whilst the FAERS dataset was characterized by a dramatic increase of the ADRs collected over the last 18 months, and particularly from 2016. Some 127,313 ADRs (referring to n = 6,161 patients/single cases) related to fentanyl’s misuse/abuse/dependence/withdrawal issues were reported to EMA, with 14,287 being judged by the reporter as “suspect.” The most represented ADRs were: “drug dependence “(76.87%), “intentional product misuse” (13.06%), and “drug abuse” (7.45%). Most cases involved adult males and the concomitant use of other prescribing/illicit drugs. A range of idiosyncratic (i.e., ingestion/injection of transdermal patches’ fentanyl) and very high-dosage intake cases were here identified. Significant numbers of cases required either a prolonged hospitalization (192/559 = 34.35%) or resulted in death (185/559 = 33.09%). Within the same time frame, YCS collected some 3,566 misuse/abuse/dependence/withdrawal ADRs, corresponding to 1,165 single patients/cases, with those most frequently reported being “withdrawal,” “intentional product misuse,” and “overdose” ADRs. Finally, FAERS identified a total of 19,145 misuse/abuse/dependence/withdrawal-related cases, being “overdose,” withdrawal, and “drug use disorder/drug abuse/drug diversion” the most represented ADRs (respectively, 43.11, 20.80, and 20.29%).Conclusion: Fentanyl abuse may be considered a public health issue with significant implications for clinical practice. Spontaneous pharmacovigilance reporting systems should be considered for mapping new trends of drug abuse.

Introduction: Cognitive enhancers (CEs), also known as “smart drugs”, “study aids” or “nootropics” are a cause of concern. Recent research studies investigated the use of CEs being taken as study aids by university students. This manuscript provides an overview of popular CEs, focusing on a range of drugs/substances (e.g., prescription CEs including amphetamine salt mixtures, methylphenidate, modafinil and piracetam; and non-prescription CEs including caffeine, cobalamin (vitamin B12), guarana, pyridoxine (vitamin B6) and vinpocetine) that have emerged as being misused. The diverted non-prescription use of these molecules and the related potential for dependence and/or addiction is being reported. It has been demonstrated that healthy students (i.e., those without any diagnosed mental disorders) are increasingly using drugs such as methylphenidate, a mixture of dextroamphetamine/amphetamine, and modafinil, for the purpose of increasing their alertness, concentration or memory. Aim: To investigate the level of knowledge, perception and impact of the use of a range of CEs within Higher Education Institutions. Methodology: A systematic review was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Whilst 1400 studies were identified within this study through a variety of electronic databases (e.g., 520 through PubMed, 490 through Science Direct and 390 through Scopus), 48 papers were deemed relevant and were included in this review. Results: The most popular molecules identified here included the stimulant CEs, e.g., methylphenidate, modafinil, amphetamine salt mixtures and caffeine-related compounds; stimulant CEs’ intake was more prevalent among males than females; drugs were largely obtained from friends and family, as well as via the Internet. It is therefore suggested that CEs are increasingly being used among healthy individuals, mainly students without any diagnosed cognitive disorders, to increase their alertness, concentration, or memory, in the belief that these CEs will improve their performance during examinations or when studying. The impact of stimulant CEs may include tolerance, dependence and/or somatic (e.g., cardiovascular; neurological) complications. Discussion: The availability of CEs for non-medical indications in different countries is influenced by a range of factors including legal, social and ethical factors. Considering the risk factors and motivations that encourage university students to use CE drugs, it is essential to raise awareness about CE-related harms, counteract myths regarding “safe” CE use and address cognitive enhancement in an early stage during education as a preventative public health measure.

(1) Introduction: Drug-related deaths in the UK are at concerning high levels. The unknown content and purity of illicit substances can cause unpredictable adverse effects and thus a public health risk with no sign of abating. On-site drug checking is a public health strategy that has previously been implemented, predominantly in festival settings, but without Home Office licensing. (2) Aims: The aim of this study was to pilot the UK’s first pharmacist-led, Home Office-licensed community drug checking service. (3) Methods: A bespoke protocol incorporating legally, professionally and ethically binding documents was implemented. This free, confidential service ran between February and March 2019, was available to anyone over 18 who were purposefully recruited, gave informed consent and agreed to relinquish their drug sample. Samples were checked on-site within an established Substance Misuse Service (SMS) using a handheld Raman spectrometer to determine likely drug content and adulterants. In parallel, participants completed a questionnaire about their substance use and the drug sample(s) being tested. A pharmacist-led multidisciplinary approach was adopted to discuss the analytical findings. Informed by the results of the analysis and the questionnaire, people who used the service received tailored harm reduction advice. (4) Results and Discussion: The pilot operated for a total of four days over four weeks. Eleven people visited and relinquished a total of thirteen samples. Half of the participants had previously overdosed and were known to the SMS. Seventy per cent were male, all were White British individuals, 30% were employed and two people disclosed visiting from another nearby town. Samples included what was thought to be heroin, synthetic cannabinoids, stimulants, benzodiazepines and LSD and none required activation of the “alerts cascade” process. Most participants drank alcohol regularly and the concomitant use of traditional illicit drugs and prescribed medication (including opioids, anxiolytics and antidepressants) with sedating profiles was common. Given some of the ethical decisions and interpretation of the results, specialist pharmacist involvement was deemed essential. (5) Conclusions: This pilot demonstrated the proof-of-concept that a pharmacist-led Home Office-licensed drug checking service can be successfully implemented in community SMSs.

Objective: This survey aimed to explore knowledge and experience on novel psychoactive substances (NPS) of healthcare professionals (HCPs). The study also aimed to assess how HCPs would like to improve their knowledge of NPS. Methods: Seventy paper questionnaires were disseminated in 2017 within continuing education events to pharmacists, nurses and general practitioners (GPs). Additionally, 127 online surveys were completed using the Qualtrics platform by other HCPs and mental health nurses in six United Kingdom (UK) independent mental health hospitals long-stay in-patient rehabilitation services. Two educational sessions involving pharmacists and GPs were also held in late 2017 and mid-2018. Knowledge of NPS by HCPs was evaluated prior to the start of the educational events. Evaluation forms were handed out post-sessions to garner feedback, especially on areas for improvement for future sessions. Statistical analysis of data was undertaken using SPSS (V.25). Results: Most HCPs reported only ‘basic’ to ‘intermediate’ NPS knowledge. Substance misuse service staff felt more informed, were more often consulted and had greater confidence regarding NPS compared to hospital and primary care professionals. A negative association was found between the age of the HCP and knowledge of NPS. Most participants expressed a need for regular training and updates as insufficient NPS-related information is currently received. Conclusions: An improvement within the self-reported knowledge of HCPs on NPS is evident in comparison to previous studies. Continued education of HCPs on NPS is fundamental for the provision of improved harm reduction services, which can enhance overall care for NPS service users.

Background: Clozapine is of high clinical relevance for the management of both treatment-resistant schizophrenia and psychotic disturbances with concurrent drug misuse. Although the molecule presents with a range of well-known side-effects, its discontinuation/withdrawal syndrome has been only anecdotally described. Aims: the 2005−2018 European Medicines Agency (EMA) dataset of Adverse Drug Reactions (ADRs) was analyzed to identify and describe possible clozapine withdrawal- and misuse-/abuse-/dependence-related issues. Method: A descriptive analysis of clozapine-related ADRs was performed when available, data on ADRs’ outcome, dosage, and possible concomitant drug(s) were considered. Results: Out of 11,847 clozapine-related ADRs, some 599 (5.05%) were related to misuse/abuse/dependence/withdrawal issues, including 258 withdrawal-related (43.1%); 241 abuse-related (40.2%); and 80 intentional product misuse-related (13.3%) ADRs. A small number of overdose- and suicide-related ADRs were reported as well. Clozapine was typically (69.2%) identified alone, and most (84.7%) fatalities/high-dosage intake instances were reported in association with a history of substance abuse. Conclusions: Previous suggestions about the possibility of a clozapine discontinuation/withdrawal occurrence are here supported, but further studies are needed. However, the misuse/abuse cases here identified might be difficult to interpret, given the lack of studies highlighting the possible recreational use of clozapine. The high-dosage intake, fatal outcomes and clozapine/polydrug abuse issues reported here may, however, be a reason for concern.

Currently different classes of psychoactive substances are easily available for abuse, including several hundred novel psychoactive substances (NPS). Some of these drugs occur naturally in plants and animals or are chemically modified from plant or animal compounds and have been abused by humans over millennia. Recently, the occurrence of a new “drug culture” (e.g., psychonauts) who consume a great variety of NPS with hallucinogenic/psychedelic properties, facilitated the development of a new “psychedelic trend” toward the consumption of substances contained in some species of animals (“psychedelic fauna”). The present review aims at providing an overview of the most commonly abused “psychedelic animals,” by combining a dual search strategy coming from online psychonauts' experiences and English literature searches on the PubMed/Medline Google Scholar databases. A multilingual qualitative assessment on a range of websites and online resources was performed in order to identify a list of animals who possess some psychoactive properties and could be abused by humans for recreational purposes. Several species are implicated (i.e., ants, amphibians, fish). Routes of administration depend on the animal, substance included, metabolism, toxicity and individual, social and cultural variability. Online purchase and access are easy through tourism-related search strategies (“frog trip,” “help of charmer snake,” “religious trip”).

Hallucinogen-persisting perception disorder (HPPD) is a syndrome characterized by prolonged or reoccurring perceptual symptoms, reminiscent of acute hallucinogen effects. HPPD was associated with a broader range of LSD (lysergic acid diethylamide)-like substances, cannabis, methylenedioxymethamphetamine (MDMA), psilocybin, mescaline, and psychostimulants. The recent emergence of novel psychoactive substances (NPS) posed a critical concern regarding the new onset of psychiatric symptoms/syndromes, including cases of HPPD. Symptomatology mainly comprises visual disorders (i.e., geometric pseudo-hallucinations, haloes, flashes of colors/lights, motion-perception deficits, afterimages, micropsia, more acute awareness of floaters, etc.), even though depressive symptoms and thought disorders may be comorbidly present. Although HPPD was first described in 1954, it was just established as a fully syndrome in 2000, with the revised fourth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). HPPD neural substrates, risk factors, and aetiopathogenesys still largely remain unknown and under investigation, and many questions about its pharmacological targets remain unanswered too. A critical mini review on psychopathological bases, etiological hypothesis, and psychopharmacological approaches toward HPPD, including the association with some novel substances, are provided here, by means of a literature search on PubMed/Medline, Google Scholar, and Scopus databases without time restrictions, by using a specific set of keywords. Pharmacological and clinical issues are considered, and practical psychopharmacological recommendations and clinical guidelines are suggested.

Recently, a range of prescription and over-the-counter drugs have been reportedly used as Novel Psychoactive Substances (NPS), due to their potential for abuse resulting from their high dosage/idiosyncratic methods of self-administration. This paper provides a systematic review of the topic, focusing on a range of medications which have emerged as being used recreationally, either on their own or in combination with NPS. Among gabapentinoids, pregabalin may present with higher addictive liability levels than gabapentin, with pregabalin being mostly identified in the context of opioid, polydrug intake. For antidepressants, their dopaminergic, stimulant-like, bupropion activities may explain their recreational value and diversion from the therapeutic intended use. In some vulnerable clients, a high dosage of venlafaxine (‘baby ecstasy’) is ingested for recreational purposes, whilst the occurrence of a clinically-relevant withdrawal syndrome may be a significant issue for all venlafaxine-treated patients. Considering second generation antipsychotics, olanzapine appears to be ingested at very large dosages as an ‘ideal trip terminator’, whilst the immediate-release quetiapine formulation may possess proper abuse liability levels. Within the image- and performance- enhancing drugs (IPEDs) group, the beta-2 agonist clenbuterol (‘size zero pill’) is reported to be self-administered for aggressive slimming purposes. Finally, high/very high dosage ingestion of the antidiarrhoeal loperamide has shown recent increasing levels of popularity due to its central recreational, anti-withdrawal, opiatergic effects. The emerging abuse of prescription drugs within the context of a rapidly modifying drug scenario represents a challenge for psychiatry, public health and drug-control policies.

Substance misuse services need to meet the growing demand and needs of individuals using new psychoactive substances (NPS). A review of the literature identified a paucity of research regarding NPS use by these individuals and UK guidelines outline the need for locally tailored strategies. The purpose of this qualitative study was to identify and explore key themes in relation to the use of NPS by individuals receiving community treatment for their substance use. Electronic records identified demographics and semi-structured interviews were undertaken. A thematic analysis of transcripts identified a variety of substance use histories; 50% were prescribed opiate substitutes and 25% used NPS as a primary substance. All were males, age range 26–59 years (SD = 9), who predominantly smoked cannabinoids and snorted/injected stimulant NPS. The type of NPS used was determined by affordability, availability, side-effect profile and desired effects (physical and psychological: 25% reported weight loss as motivation for their use). Poly-pharmacy, supplementation and displacement of other drugs were prevalent. In conclusion, NPS use and associated experiences vary widely among people receiving substance use treatment. Development of effective recovery pathways should be tailored to individuals, and include harm reduction strategies, psychosocial interventions, and effective signposting. Services should be vigilant for NPS use, “on top” use and diversion of prescriptions.