Exploring the Potential Impact of GLP-1 Receptor Agonists on Substance Use, Compulsive Behavior, and Libido: Insights from Social Media Using a Mixed-Methods Approach.

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.

New trends of drug abuse in custodial settings: A systematic review on the misuse of over-the-counter drugs, prescription-only-medications, and new psychoactive substances.

The article presents a systematic literature review on the use and the psychiatric implications of over-the-counter drugs (OTC), prescription-only-medications (POM), and new psychoactive substances (NPS) within custodial settings. The searches wer carried out on 2 November 2022 on PubMed, Scopus, and Web of Science in line with PRISMA guidelines. A total of 538 records were identified, of which 37 met the inclusion criteria. Findings showed the most prevalent NPS and OTC and POM classes reported in prisons were synthetic cannabinoids receptor agonists (SCRAs) and opioids, respectively. NPS markets were shown to be in constant evolution following the pace of legislations aimed to reduce their spread. The use of such substances heavily impacts the conditions and rehabilitation of persons in custody, with consequent physical and mental health risks. It is important to raise awareness of the use and misuse of such substances in prisons (i) from an early warning perspective for law enforcement and policy makers (ii) to prompt doctors to cautiously prescribe substances that may be misused (iii) to improve and increase access to treatment provided (iv) to add such substances to routine toxicological screening procedures (v) to improve harm reduction programmes.

GLP-1 Receptor Agonists and Related Mental Health Issues; Insights from a Range of Social Media Platforms Using a Mixed-Methods Approach.

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.

Is There a Risk for Semaglutide Misuse? Focus on the Food and Drug Administration's FDA Adverse Events Reporting System (FAERS) Pharmacovigilance Dataset.

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.

In silico studies on recreational drugs: 3D quantitative structure activity relationship prediction of classified and de novo designer benzodiazepines.

Currently, increasing availability and popularity of designer benzodiazepines (DBZDs) constitutes a primary threat to public health. To assess this threat, the biological activity/potency of DBZDs was investigated using in silico studies. Specific Quantitative Structure Activity Relationship (QSAR) models were developed in Forge™ for the prediction of biological activity (IC50 ) on the γ-aminobutyric acid A receptor (GABA-AR) of previously identified classified and unclassified DBDZs. A set of new potential ligands resulting from scaffold hopping studies conducted with MOE® was also evaluated. Two generated QSAR models (i.e. 3D-field QSAR and RVM) returned very good performance statistics (r2  = 0.98 [both] and q2  = 0.75 and 0.72, respectively). The DBZDs predicted to be the most active were flubrotizolam, clonazolam, pynazolam and flucotizolam, consistently with what reported in literature and/or drug discussion fora. The scaffold hopping studies strongly suggest that replacement of the pendant phenyl moiety with a five-membered ring could increase biological activity and highlight the existence of a still unexplored chemical space for DBZDs. QSAR could be of use as a preliminary risk assessment model for (newly) identified DBZDs, as well as scaffold hopping for the creation of computational libraries that could be used by regulatory bodies as support tools for scheduling procedures.

Contribution of Drugs to Drowning in Scotland from 1996 to 2020.

OBJECTIVE: Psychoactive substance use (including alcohol) can affect risk perception, leading to accidents and deaths. There is little detailed or up-to-date information on the role of drugs in drownings in the United Kingdom (UK). This Scottish case-study aimed to fill this knowledge gap. METHODS: Anonymised data for individual drug-poisoning-related drowning registered from 1996 to 2020 were provided by the National Records of Scotland. Statistical analyses were performed for socio-demographics, ICD coding, cause of death, and substances implicated. RESULTS: It has been reported that death registrations increased from 7 in 2017 to over 20 during 2019-20. These deaths (n=160) accounted for <1% of all drug-related poisoning deaths; this proportion rose to record levels (c.1.5%) during 2019-20. Most deaths (69%) involved males. The mean age was 39.8 (range 16-81, SD 15.0) years. The main drug classes implicated were: opiates/opioids (41%), benzodiazepines (31%), stimulants (19%), and antidepressants (14%). Moreover, 57% of benzodiazepines were 'designer' drugs. CONCLUSION: Scottish drownings associated with drug consumption are increasing rapidly. It has been observed that central nervous system depressant drugs (e.g., opioids, benzodiazepines, alcohol) are often involved in drowning. 'Designer' benzodiazepines are a principal factor in increasing Scottish drug-related poisoning deaths; they may be partially responsible for increasing numbers of related drownings. Evidence-based strategies to further reduce the number of preventable drownings should include reference to the dangers of drugs.

First Death Involving 4-Fluoroethylphenidate (4F-EPH): Case Report, User Experiences, and Review of the Related Literature.

Background: 4-Fluoroethylphenidate (4F-EPH) is a psychoactive substance, sold primarily over the Internet as a `research chemical'. Recreational and `functional' use of this drug has been reported by online user fora. Scientifically-based data on the pharmacological, physiological, psychopharmacological, toxicological, and epidemiological characteristics of this molecule is non-existent. The aim of this paper is to remedy this situation. Methods: Recent literature (including 'grey') was searched to update what is known about 4F-EPH, especially its toxicity. This was supplemented by netnographic examinations of internet sites. Results: The resultant information is presented, including details of the first reported death involving 4F-EPH use in 2016. There are no international controls imposed on 4F-EPH. However, it has been made a controlled drug in several European countries, including the United Kingdom since 31 May 2017, as well as Canada. Conclusions: It is vital that any other cases, including non-fatal overdoses, are documented so that a firmer scientific evidence-base can be established for this molecule. This will then help inform clinical practice.

Alprazolam-related deaths in Scotland, 2004-2020.

BACKGROUND: The benzodiazepine drug alprazolam, a fast-acting tranquiliser, cannot be prescribed on the National Health Service in the United Kingdom. Illicit alprazolam supply and consumption have increased. Concern about increasing numbers of alprazolam-related fatalities started circulating in 2018. However, statistics on this issue are very limited. This study examined patterns in such mortality in Scotland. METHODS: Statistics on deaths where alprazolam was mentioned in the 'cause of death' were obtained from official mortality registers. Anonymised Scottish case-level data were obtained. Data were examined in respect of the characteristics of decedents and deaths using descriptive statistics. RESULTS: Scotland registered 370 deaths in 2004-2020; 366 of these occurred in 2015-2020: most involved males (77.1%); mean age 39.0 (SD 12.6) years. The principal underlying cause of death was accidental poisoning: opiates/opioids (77.9%); sedatives/hypnotics (15.0%). Two deaths involved alprazolam alone. Main drug groups implicated: opiates/opioids (94.8%), 'other benzodiazepines' (67.2%), gabapentinoids (42.9%), stimulants (30.1%), antidepressants (15.0%). Two-thirds (64.2%) involved combinations of central nervous system (CNS) depressants. DISCUSSION: Alprazolam-related deaths are likely due to an increasing illicit supply. The fall in deaths in 2019-2020 is partially due to increased use of designer benzodiazepines. Treatment for alprazolam dependence is growing. Clinicians need to be aware of continuing recreational alprazolam use. When such consumption occurs with CNS depressants, overdose and death risks increase. CONCLUSIONS: More awareness of alprazolam contributing to deaths, especially in conjunction with other CNS depressants, is needed by consumers and clinicians. Improved monitoring of illicit supplies could identify emerging issues of medicines' abuse.

A Focus on Abuse/Misuse and Withdrawal Issues with Selective Serotonin Reuptake Inhibitors (SSRIs): Analysis of Both the European EMA and the US FAERS Pharmacovigilance Databases.

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.

Designer Benzodiazepines' Activity on Opioid Receptors: A Docking Study.

BACKGROUND: Previous studies have reported that benzodiazepines (BZDs) seem to enhance euphoric and reinforcing properties of opioids in opioid users so that a direct effect on opioid receptors has been postulated, together with a possible synergistic induction of severe side effects due to co use of BDZs and opioids. This is particularly worrisome given the appearance on the market of designer benzodiazepines (DBZDs), whose activity/toxicity profiles are scarcely known. OBJECTIVES: This study aimed to evaluate, through computational studies, the binding affinity (or lack thereof) of 101 DBZDs identified online on the kappa, mu, and delta opioid receptors (K, M, DOR); and to assess whether their mechanism of action could include activation of the latter. METHODS: MOE® was used for the computational studies. Pharmacophore mapping based on strong opioids agonist binders' 3D chemical features was used to filter the DBZDs. Resultant DBZDs were docked into the crystallised 3D active conformation of KOR (PDB6B73), DOR (PDB6PT3) and MOR (PDB5C1M). Co-crystallised ligands and four strong agonists were used as reference compounds. A score (S, Kcal/mol) representative of the predicted binding affinity, and a description of ligand interactions were obtained from MOE®. RESULTS: The docking results, filtered for S < -8.0 and the interaction with the Asp residue, identified five DBZDs as putative binders of the three ORs : ciclotizolam, fluloprazolam, JQ1, Ro 48-6791, and Ro 48-8684. CONCLUSION: It may be inferred that at least some DBZDs may have the potential to activate opioid receptors. This could mediate/increase their anxiolytic, analgesic, and addiction potentials, as well as worsen the side effects associated with opioid co-use.

Benefits and Harms of 'Smart Drugs' (Nootropics) in Healthy Individuals.

'Smart drugs' (also known as 'nootropics' and 'cognitive enhancers' [CEs]) are being used by healthy subjects (i.e. students and workers) typically to improve memory, attention, learning, executive functions and vigilance, hence the reference to a 'pharmaceutical cognitive doping behaviour'. While the efficacy of known CEs in individuals with memory or learning deficits is well known, their effect on non-impaired brains is still to be fully assessed. This paper aims to provide an overview on the prevalence of use; putative neuroenhancement benefits and possible harms relating to the intake of the most popular CEs (e.g. amphetamine-type stimulants, methylphenidate, donepezil, selegiline, modafinil, piracetam, benzodiazepine inverse agonists, and unifiram analogues) in healthy individuals. CEs are generally perceived by the users as effective, with related enthusiastic anecdotal reports; however, their efficacy in healthy individuals is uncertain and any reported improvement temporary. Conversely, since most CEs are stimulants, the related modulation of central noradrenaline, glutamate, and dopamine levels may lead to cardiovascular, neurological and psychopathological complications. Furthermore, use of CEs can be associated with paradoxical short- and long-term cognitive decline; decreased potential for plastic learning; and addictive behaviour. Finally, the non-medical use of any potent psychotropic raises serious ethical and legal issues, with nootropics having the potential to become a major public health concern. Further studies investigating CE-associated social, psychological, and biological outcomes are urgently needed to allow firm conclusions to be drawn on the appropriateness of CE use in healthy individuals.

Misuse of Anticholinergic Medications: A Systematic Review.

(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 Psychonauts' Benzodiazepines; Quantitative Structure-Activity Relationship (QSAR) Analysis and Docking Prediction of Their Biological Activity.

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.

COVID-19 Pandemic Impact on Substance Misuse: A Social Media Listening, Mixed Method Analysis.

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.

New Psychoactive Substances and Suicidality: A Systematic Review of the Current Literature.

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.

Recreational ketamine-related deaths notified to the National Programme on Substance Abuse Deaths, England, 1997-2019.

BACKGROUND: Ketamine is a phencyclidine derivative with dissociative anaesthetic properties. Increasing numbers of individuals in England take ketamine recreationally. Information on deaths arising from such use in England is presented. METHODS: Cases were extracted on 31 January 2020 from the National Programme on Substance Abuse Deaths database, based on text searches of the cause of death, coroner's verdict and positive toxicology results for the terms 'ketamine' or 'norketamine'. FINDINGS: During 1997-2005, there were <5 deaths p.a. in which ketamine was implicated. Numbers increased until 2009 (21), plateauing until 2016; thereafter, deaths have risen to about 30 p.a. Decedents' characteristics (N = 283): male 84.1%, mean age 31.2 (SD 10.0) years, employed 56.5%, drug use history 79.6% and living with others 60.3%. Ketamine was detected with other substances in most cases. Main (74.6%) underlying cause of death was accidental poisoning. Ketamine may have impaired judgement in other cases. CONCLUSIONS: Although controlled, recreational ketamine use and related fatalities continue to increase. Consumers need to be more aware of the potentially fatal risks they face.

Psychonauts' psychedelics: A systematic, multilingual, web-crawling exercise.

Psychedelics alter the perception of reality through agonist or partial agonist interaction with the 2A serotoninergic receptor. They are classified as phenethylamines, tryptamines and lysergamides. These classes, according to the United Nations Office on Drugs and Crime (UNODC) and European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), account for an important percentage of the new psychoactive substances (NPS) current scenario.The paper aimed at: a) identifying and categorising psychedelic molecules from a list of psychonaut websites and NPS online resources; and b) comparing the NPSfinderⓇ results with those from the European and United Nations databases. A crawling software (i.e. 'NPSfinderⓇ') was created to automatically scan, 24/7, a list of URLs and to extract a range of information (chemical/street names, chemical formulae, etc.) to facilitate NPS identification. Data collected were manually analysed and compared with the EMCDDA and UNODC databases.The overall number of psychedelic NPS detected by NPSfinderⓇ (November 2017-February 2020) was 1344, almost ten-times higher than that reported by the UNODC and EMCDDA combined. Of these, 994 previously unknown molecules were identified as (potential) novel psychedelics, suggesting a strong discrepancy between online and real-world NPS scenarios. The results show the interest of psychonauts, and maybe of the much larger community of 'recreational' drug users, towards psychedelics. Moreover, examining online scenario may help in assessing the availability in the real world of psychedelic NPS; understanding drug trends; and in possibly predicting future drug scenarios.

New psychoactive substances (NPS) and serotonin syndrome onset: A systematic review.

The use of several new psychoactive substances (NPS) has become very popular and is posing global health risks. Chemically and pharmacologically diverse molecules are constantly emerging and are presenting with a wide range of clinical implications. Serotonin toxicity, and specifically Serotonin Syndrome (SS), might develop as a result of an over-activation of the serotoninergic system caused by several mechanisms resulting in a classic triad of altered mental status, neuromuscular effects, and autonomic hyperactivity. In the present systematic review, we have investigated and summarized the available evidence related to the association between SS and NPS intake. Three retrospective studies, two case series and five case reports were included in this systematic review; several NPS were found to be implicated in SS occurrence These include psychedelic phenethylamines, e.g. 2, 5-dimethoxy-4-iodophenethylamine (2C-I); 2-(4-Iodo-2,5-dimethoxyphenyl)- N-I[(2-methyoxyphenyl)methyl]ethanamine (25I-NBOMe); and 5-(2-aminopropyl)indole (5-IT); and synthetic cathinones, e.g. mephedrone; 3,4-methylenedioxypyrovalerone (MDPV); methylone; butylone; NRG3; alpha-methyltryptamine (AMT); methoxphenidine (MXP); and the antidepressant bupropion. Bupropion was here misused at high dosages and/or in combination with other licit/illicit serotonergic drugs. Whilst most substances were ingested orally, nasal insufflation (with both 5-IT and 2C-I) and sublingual administration of blotter paper (with 25I-NBOMe) were reported as well. Interestingly, the psychiatric history was negative for most subjects, apart from two cases. Clinicians should be aware of NPS potential risks and the severe consequences of their recreational use, including SS. Also, due to their undetectability in routine and common drug screenings, the diagnostic challenges posed by NPS should not be underestimated during the treatment of such patients.

Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.

BACKGROUND: Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents. OBJECTIVE: We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database. METHODS: After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234). RESULTS: The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used. CONCLUSION: Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.