The Possible Role of Prescribing Medications, Including Central Nervous System Drugs, in Contributing to Male-Factor Infertility (MFI): Assessment of the Food and Drug Administration (FDA) Pharmacovigilance Database.

BACKGROUND: A wide range of medications may have a possible role in the development of male-factor infertility (MFI), including various antineoplastic agents, testosterone/anabolic steroids, immunosuppressive drugs/immunomodulators, glucocorticosteroids, non-steroidal anti-inflammatory drugs, opiates, antiandrogenic drugs/5-alpha-reductase inhibitors, various antibiotics, antidepressants, antipsychotics, antiepileptic agents and others. We aimed at investigating this issue from a pharmacovigilance-based perspective. METHODS: The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried to identify the drugs associated the most with MFI individual reports. Only those drugs being associated with more than 10 MFI reports were considered for the disproportionality analysis. Proportional Reporting Ratios (PRRs) and their confidence intervals were computed for all the drugs identified in this way in January 2023. Secondary, 'unmasking', dataset analyses were carried out as well. RESULTS: Out of the whole database, 955 MFI reports were identified, 408 (42.7%) of which were associated with 20 medications, which had more than 10 reports each. Within this group, finasteride, testosterone, valproate, diethylstilbestrol, mechloretamine, verapamil, lovastatin and nifedipine showed significant levels of actual disproportionate reporting. Out of these, and before unmasking, the highest PRR values were identified for finasteride, diethylstilbestrol and mechloretamine, respectively, with values of 16.0 (12.7-20.3), 14.3 (9.1-22.4) and 58.7 (36.3-95.9). CONCLUSIONS: A variety of several medications, a number of which were already supposed to be potentially linked with MFI based on the existing evidence, were associated with significant PRR levels for MFI in this analysis. A number of agents which were previously hypothesized to be associated with MFI were not represented in this analysis, suggesting that drug-induced MFI is likely under-reported to regulatory agencies. Reproductive medicine specialists should put more effort into the detection and reporting of these adverse drug reactions.

Medications mostly associated with priapism events: assessment of the 2015-2020 Food and Drug Administration (FDA) pharmacovigilance database entries.

A range of drugs have a direct role in triggering ischaemic priapism. We aimed at identifying: a) which medications are associated with most priapism-reports; and, b) within these medications, comparing their potential to elicit priapism through a disproportionality analysis. The FDA Adverse Event Reporting System (FAERS) database was queried to identify those drugs associated the most with priapism reports over the last 5 years. Only those drugs being associated with a minimum of 30 priapism reports were considered. The Proportional Reporting Ratios (PRRs), and their 95% confidence intervals were computed. Out of the whole 2015-2020 database, 1233 priapism reports were identified, 933 of which (75.7%) were associated with 11 medications with a minimum of 30 priapism-reports each. Trazodone, olanzapine and tadalafil showed levels of disproportionate reporting, with a PRR of 9.04 (CI95%: 7.73-10.58), 1.55 (CI95%: 1.27-1.89), and 1.42 (CI95%: 1.10-1.43), respectively. Most (57.5%) of the reports associated with the phosphodiesterase type 5 inhibitors (PDE5Is) were related with concomitant priapism-eliciting drugs taken at the same time and/or inappropriate intake/excessive dosage. Patients taking trazodone and/or antipsychotics need to be aware of the priapism-risk; awareness among prescribers would help in reducing priapism-related detrimental sequelae; PDE5I-intake is not responsible for priapism by itself, when appropriate medical supervision is provided.

Is medicinal ketamine associated with urinary dysfunction issues? Assessment of both the European Medicines Agency (EMA) and the UK Yellow Card Scheme pharmacovigilance database-related reports.

OBJECTIVE: A range of ketamine-induced uropathy (KIU) issues have been typically described in ketamine misusers. Conversely, more knowledge is needed in terms of medicinal ketamine-related urological disturbances, since ketamine prescribing is being increasingly considered for a range of medical and psychopathological conditions. METHODS: To assess medicinal KIU issues, we aimed at analyzing both the 2005-2017 European Medicines Agency (EMA) and the 2006-2018 UK Yellow Card Scheme (YCS) pharmacovigilance databases. RESULTS: A total number (eg, all categories) of 11 632 EMA ketamine-related adverse drug reaction (ADR) reports were here identified. Out of these, some 9971 ADRs (eg, 85.7% of the total) were judged as "suspect" and were here analyzed. Some 1758 ADRs (17.7% of 9971, corresponding to 194 individual patients) referred to urological issues, relating to either kidney/ureter (922 ADRs) or bladder/urethra (837 ADRs). Ketamine was the sole drug administered in 156/194 (80.4%) cases/patients. Although most cases occurred in the 1 month-1 year time frame following the start of ketamine prescribing, in 30 cases the ADR occurred within 48 hours. Most ADR-related cases resolved, although both sequelae (18 cases) and fatalities (79/1758; 4.5%) were recorded. Overall, YCS data were consistent with EMA findings, with some 50/217 (23%) ADRs referring to renal/urinary disorders. CONCLUSIONS: Current data may only represent a gross underestimate of the KIU real prevalence issues. It is here suggested that chronic treatment involving higher doses/repeated exposure to ketamine be restricted to the context of controlled trials or clinical audits.

The e-Psychonauts' 'Spiced' World; Assessment of the Synthetic Cannabinoids' Information Available Online.

BACKGROUND: A wide range of novel psychoactive substances (NPS) is regularly searched and discussed online by web-based drug enthusiasts (i.e. the e-psychonauts). Among NPS, the range of synthetic cannabinoids (SC; 'Spice') currently represents a challenge for governments and clinicians. METHODS: Using a web crawler (i.e. the NPS.Finder®), the present study aimed at assessing psychonauts' fora/platforms to better understand the online mentions of SC. RESULTS: The open-web crawling/navigating software identified here some 1,103 synthetic cannabinoids. Of these, 863 molecules were not listed in either the international or the European NPS databases. CONCLUSION: A web crawling approach helped here in identifying a large range of unknown SC likely to possess a misuse potential. Most of these novel/emerging molecules are still relatively unknown. This is a reason for concern; each of these analogues potentially presents 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 SC-associated public health risks.

ß-2 Agonists as Misusing Drugs? Assessment of both Clenbuterol- and Salbutamol-related European Medicines Agency Pharmacovigilance Database Reports.

A recent years' increase in misusing levels of image- and performance- enhancing drugs (IPEDs) has been observed. Out of these drugs, beta-2 agonists have recently emerged for their potential of misuse, especially for slimming and bodybuilding purposes. To this perspective, clenbuterol ('the size zero pill') has been reported as being both popular and widely available from the illegal market. All clenbuterol and salbutamol misuse/abuse/dependence/withdrawal/overdose/off-label spontaneous reports (2006-2016) from the European Medicines Agency (EMA) EudraVigilance (EV) database were collected and analysed by age range, gender, concomitant therapies and source of information. From the EV database, 55 of a total number of 920 'suspect' misuse/abuse/dependence/withdrawal/overdose/off-label ADRs (e.g. 5.97%; corresponding to 25 of 138 individuals) and 1310 of 62,879 ADRs (e.g. 2.08%; corresponding to 474 of 6923 individuals) were, respectively, associated with clenbuterol (typically ingested in combination with a range of anabolic steroids) and salbutamol. Proportional reporting ratio (PRR) value for misuse/abuse ADRs was higher (PRR = 18.38) for clenbuterol in comparison with salbutamol. Clenbuterol misuse/abuse could be a cause for major concern, especially in vulnerable individuals.

An insight into the deep web; why it matters for addiction psychiatry?

OBJECTIVE: Nowadays, the web is rapidly spreading, playing a significant role in the marketing or sale or distribution of "quasi" legal drugs, hence facilitating continuous changes in drug scenarios. The easily renewable and anarchic online drug-market is gradually transforming indeed the drug market itself, from a "street" to a "virtual" one, with customers being able to shop with a relative anonymity in a 24-hr marketplace. The hidden "deep web" is facilitating this phenomenon. The paper aims at providing an overview to mental health's and addiction's professionals on current knowledge about prodrug activities on the deep web. METHODS: A nonparticipant netnographic qualitative study of a list of prodrug websites (blogs, fora, and drug marketplaces) located into the surface web was here carried out. A systematic Internet search was conducted on Duckduckgo® and Google® whilst including the following keywords: "drugs" or "legal highs" or "Novel Psychoactive Substances" or "NPS" combined with the word deep web. RESULTS: Four themes (e.g., "How to access into the deepweb"; "Darknet and the online drug trading sites"; "Grams-search engine for the deep web"; and "Cryptocurrencies") and 14 categories were here generated and properly discussed. CONCLUSIONS: This paper represents a complete or systematical guideline about the deep web, specifically focusing on practical information on online drug marketplaces, useful for addiction's professionals.

From concept(ion) to life after death/the grave: The 'natural' history and life cycle(s) of novel psychoactive substances (NPS).

A range of information needs should be met in order to better understand and predict the longevity/existence of novel psychoactive substances (NPS). This conceptual paper argues that one way of assessing how long a molecule may be around is to document how the life cycles or natural histories of 'traditional' drugs and NPS evolve. The earliest indication of the possible appearance of a new substance might be evidenced on the DeepWeb. However, this means they are less visible, in line with the clandestine nature of drug use and supply. Therefore, monitoring discussion groups/fora needs the development of new methods compared to those used in the Surface Net. Issues needing consideration in establishing NPS life cycles are outlined here, together with the probable outcomes that could result. The approach advocated means that it should be easier to identify which NPS are likely to come up or are emerging in real time, and, therefore, pre-empt/prevent their supply.

"Spice," "kryptonite," "black mamba": an overview of brand names and marketing strategies of novel psychoactive substances on the web.

UNLABELLED: Abstract Introduction: Novel Psychoactive Substances (NPSs) are often sold online as "legal" and "safer" alternatives to International Controlled Drugs (ICDs) with captivating marketing strategies. Our aim was to review and summarize such strategies in terms of the appearance of the products, the brand names, and the latest trends in the illicit online marketplaces. METHODS: Scientific data were searched in PsychInfo and Pubmed databases; results were integrated with an extensive monitoring of Internet (websites, online shops, chat rooms, fora, social networks) and media sources in nine languages (English, French, Farsi, Portuguese, Arabic, Russian, Spanish, and Chinese simplified/traditional) available from secure databases of the Global Public Health Intelligence Network. RESULTS: Evolving strategies for the online diffusion and the retail of NPSs have been identified, including discounts and periodic offers on chosen products. Advertisements and new brand names have been designed to attract customers, especially young people. An increased number of retailers have been recorded as well as new Web platforms and privacy systems. DISCUSSION: NPSs represent an unprecedented challenge in the field of public health with social, cultural, legal, and political implications. Web monitoring activities are essential for mapping the diffusion of NPSs and for supporting innovative Web-based prevention programmes.

Classical and novel psychoactive substances: rethinking drug misuse from an evolutionary psychiatric perspective.

In this article, ontogenetic and phylogenetic causes of drug abuse and links to human emotional development are considered. Some evolutionary perspectives (e.g. that under certain conditions, consumption of otherwise toxic alkaloids may confer both physical and cultural advantages) are reviewed. As described in the 'mismatch theory', the capacity of the human genome to evolve defences against toxins has been outstripped by the pace of cultural change and technological development, such as purposeful fermentation of alcohol and more recently distillation of alcohol; purification and chemical manipulation of plant alkaloids; and the engineering of entirely novel psychoactive substances (NPS). The functions of the neurobiological substrates that mediate substance misuse and dependence are reviewed. Reasons are given why NPSs present greater cause for concern than plant-derived substances of abuse. We argue that evolutionary biology provides an important orientation for the research agenda in substance misuse.

Cocaine/crack cocaine consumption, treatment demand, seizures, related offences, prices, average purity levels and deaths in the UK (1990 - 2004).

A recent trend of escalating use of cocaine/crack cocaine was observed in the UK. The number of mentions on death certificates; last year use of cocaine; treatment demand, number of drug offenders, seizures, prices and average purity levels were the indicators used for this descriptive and correlational study. Figures (1990-2004) were taken from official UK sources. A total of 1022 cocaine/crack cocaine death mentions (i.e. deaths from any cause where the presence of cocaine/crack cocaine was also detected) were identified, with cocaine/crack cocaine being the sole drug mentioned in 36% of cases. The number of cocaine/crack cocaine death mentions showed a year-on-year increase and correlated positively with the following cocaine (powder) figures: last year use (p < 0.001); number of offenders (p < 0.001) and number of seizures (p < 0.001), but correlated negatively with price (p < 0.001). Furthermore, the number of cocaine/crack cocaine death mentions correlated positively with the number of crack offenders (p < 0.001) and seizures (p < 0.001), but correlated negatively with both crack purity ( p < 0.001) and price (p < 0.05). With conditions of increasing drug availability having been met in the UK, decrease in cocaine prices were associated with higher consumption levels and this, in turn, contributed to the increase in number of cocaine-related fatalities. There are limitations with the information collected, since no distinction is usually made on medical death certificates between cocaine and crack cocaine. The present study being an ecological one, it proved difficult to address the role of confounding variables that may well explain some of the associations observed.

Online availability of dextropropoxyphene over time, 2003-2005.

Online pharmacies are increasingly common, and some of them have been reported to inappropriately supply prescription-only medicines. Dextropropoxyphene-containing compounds are addictive and frequently implicated in fatalities occurring in the United Kingdom. We aimed here at assessing the online availability of dextropropoxyphene for purchase over a time-span of 2 years (September 2003-August 2005). A Google search was run in September 2003 using different sets of keywords and the first 100 links identified were thoroughly assessed. In March 2005, the same e-pharmacies websites identified at baseline were accessed again and a Google search using the same sets of keywords previously used was run as well. Furthermore, a specialized search with Froogle was run both in March and August 2005. Although an illegal practice in most countries, a number of websites willing to sell the compound internationally were identified at the time of the baseline search. In March 2005, the Google search for vending websites identified 361,000 links, compared with 40,000 18 months before. Only half of dextropropoxyphene vending e-pharmacies were still active by March 2005 but, at that point in time, access to Froogle apparently facilitated the task of online dextropropoxyphene purchase. By August 2005, however, the same Froogle search identified only one link aimed at online dextropropoxyphene shopping. In the United Kingdom, dextropropoxyphene-related products will be withdrawn later this year but this may have only limited impact on the availability of the compound. The emergence of Internet as an unregulated source of controlled substances is an important development that may have significant public health implications. This issue needs to be dealt with at both international and national level.

Ecstasy (MDMA, MDA, MDEA, MBDB) consumption, seizures, related offences, prices, dosage levels and deaths in the UK (1994-2003).

In the last decade, a global trend of escalating ecstasy (MDMA, MDA, MDEA, MBDB) use was observed. Mentions on medical death certificates, last year's ecstasy use, number of drug offenders, seizures, prices and dosage levels figures were used for this descriptive and correlational study. Figures (1994-2003) were taken from the UK General Mortality Registers, from the Home Office Statistical Bulletins, from the British Crime Survey and from those reported to both the National Crime Intelligence and Forensic Science Services. A total of 394 ecstasy deaths mentions were here identified from the UK; in 42% of cases ecstasy was the sole drug mentioned. Overall, number of fatalities showed a year-per-year increase and positively correlated with: prevalence of last year's use (p < 0.01); number of offenders (p < 0.01) and number of seizures (p < 0.01) but negatively correlated with ecstasy price (p < 0.05). Price negatively correlated with: prevalence of last year's use (p < 0.001) and number of seizures (p < 0.01); but positively correlated with average MDMA dosage per tablet (p < 0.01). MDA, MDEA and MBDB accounted for a significant proportion of tablets only up to 1997, but not afterwards. Increasing production with a concomitant decrease in ecstasy price may have facilitated an increase in consumption levels and this, in turn, may have determined an increase in number of ecstasy deaths mentions. Only medical death certificates and not coroners' reports at the end of their inquests were here analysed; no data were available in respect of other drugs use and toxicology results.

Importance of cyberspace for the assessment of the drug abuse market: preliminary results from the Psychonaut 2002 project.

What do therapy and cybertherapy need to take into account to be effective for the treatment of drug-related disorders? The Psychonaut 2002 project is aimed to create a new and updated Web-based tool, which will be based on evolving drug scenarios, in order to provide professionals from the drug addiction field with easily accessible and reliable information. The drug abuse settings available on the Web will be described and the methodology will be discussed. Preliminary results of a search on MDMA and MDMA-like substances confirm that it is possible both to identify emerging trends and to provide information for prevention and appropriate intervention.