Structural and functional damage to the retina and skeletal muscle in Xenopus laevis embryos exposed to the commonly used psychotropic benzodiazepine delorazepam.

Benzodiazepines, psychotropic drugs, are among the most frequently found pharmaceuticals in aquatic matrices. An increasing number of studies are reporting their harmful effects on adults' behaviour and physiology, while little information is available regarding developing organisms exposed since early stages. Improper activation of GABA receptors during embryonic development is likely to induce relevant consequences on the morphogenesis and, at later stages, on behaviour. This study investigated the negative effects of three increasing concentrations of delorazepam on Xenopus laevis retinal and skeletal muscle morphogenesis. Morphological and ultrastructural investigations were correlated with gene expression, while Raman spectroscopy highlighted the main biochemical components affected. Conventional phototactic response and orientation in the magnetic field were assessed as indicators of proper interaction between sensory organs and the nervous system. Results confirm the profound impact of delorazepam on development and return an alarming picture of the amphibians' survival potentialities in a benzodiazepine-contaminated environment.

The occurrence of typical psychotropic drugs in the aquatic environments and their potential toxicity to aquatic organisms - A review.

Psychotropic drugs (PDs) and their bioactive metabolites often persist in aquatic environments due to their typical physical properties, which made them resistant to removal by traditional wastewater treatment plants (WWTPs). Consequently, such drugs and/or their metabolites are frequently detected in both aquatic environments and organisms. Even at low concentrations, these drugs can exhibit toxic effects on non-target organisms including bony fish (zebrafish (Danio rerio) and fathead minnows) and bivalves (freshwater mussels and clams). This narrative review focuses on the quintessential representatives of three different categories of PDs-antiepileptics, antidepressants, and antipsychotics. The data regarding their concentrations occurring in the environment, patterns of distribution, the degree of enrichment in various tissues of aquatic organisms, and the toxicological effects on them are summarized. The toxicological assessments of these drugs included the evaluation of their effects on the reproductive, embryonic development, oxidative stress-related, neurobehavioral, and genetic functions in various experimental models. However, the mechanisms underlying the toxicity of PDs to aquatic organisms and their potential health risks to humans remain unclear. Most studies have focused on the effects caused by acute short-term exposure due to limitations in the experimental conditions, thus making it necessary to investigate the chronic toxic effects at concentrations that are in coherence with those occurring in the environment. Additionally, this review aims to raise awareness and stimulate further research efforts by highlighting the gaps in the understanding of the mechanisms behind PD-induced toxicity and potential health risks. Ultimately, the study underscores the importance of developing advanced remediation methods for the removal of PDs in WWTPs and encourages a broader discussion on mitigating their environmental impacts.

Potential neonatal toxicity of new psychoactive substances.

Cannabis, cocaine, 3,4-methylenedioxymethamphetamine, and lysergic acid diethylamide are psychoactive substances with a significant increase in consumption during the 21st century due to their popularity in medicinal and recreational use. New psychoactive substances (NPSs) mimic established psychoactive substances. NPSs are known as being natural and safe to consumers; however, they are neither natural nor safe, causing severe adverse reactions, including seizures, nephrotoxicity, and sometimes death. Synthetic cannabinoids, synthetic cathinones, phenethylamines, and piperazines are all examples of NPSs. As of January 2020, nearly 1000 NPSs have become documented. Due to their low cost, ease of availability, and difficulty of detection, misuse of NPSs has become a familiar and growing problem, especially in adolescents and young adults in the past decade. The use of NPSs is associated with higher risks of unplanned sexual intercourse and pregnancy. As many as 4 in 100 women seeking treatment for substance abuse are pregnant or nursing. Animal studies and human clinical case reports have shown that exposure to certain NPSs during lactation periods has toxic effects on neonates, increasing various risks, including brain damage. Nevertheless, neonatal toxicity effects of NPSs are usually unrecognized and overlooked by healthcare professionals. In this review article, we introduce and discuss the potential neonatal toxicity of NPSs, emphasizing synthetic cannabinoids. Utilizing the established prediction models, we identify synthetic cannabinoids and their highly accumulative metabolites in breast milk.

Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review.

According to the EU Early Warning System (EWS), synthetic cathinones (SCs) are the second largest new psychoactive substances (NPS) class, with 162 synthetic cathinones monitored by the EU EWS. They have a similar structure to cathinone, principally found in Catha Edulis; they have a phenethylamine related structure but also exhibit amphetamine-like stimulant effects. Illegal laboratories regularly develop new substances and place them on the market. For this reason, during the last decade this class of substances has presented a great challenge for public health and forensic toxicologists. Acting on different systems and with various mechanisms of action, the spectrum of side effects caused by the intake of these drugs of abuse is very broad. To date, most studies have focused on the substances' cardiac effects, and very few on their associated neurotoxicity. Specifically, synthetic cathinones appear to be involved in different neurological events, including increased alertness, mild agitation, severe psychosis, hyperthermia and death. A systematic literature search in PubMed and Scopus databases according to PRISMA guidelines was performed. A total of 515 studies published from 2005 to 2022 (350 articles from PubMed and 165 from Scopus) were initially screened for eligibility. The papers excluded, according to the criteria described in the Method Section (n = 401) and after full text analyses (n = 82), were 483 in total. The remaining 76 were included in the present review, as they met fully the inclusion criteria. The present work provides a comprehensive review on neurotoxic mechanisms of synthetic cathinones highlighting intoxication cases and fatalities in humans, as well as the toxic effects on animals (in particular rats, mice and zebrafish larvae). The reviewed studies showed brain-related adverse effects, including encephalopathy, coma and convulsions, and sympathomimetic and hallucinogenic toxidromes, together with the risk of developing excited/agitated delirium syndrome and serotonin syndrome.

Reports of Adverse Events Associated with Use of Novel Psychoactive Substances, 2017-2020: A Review.

An important role of modern forensic and clinical toxicologists is to monitor the adverse events of novel psychoactive substances (NPS). Following a prior review from 2013 to 2016, this critical literature review analyzes and evaluates published case reports for NPS from January 2017 through December 2020. The primary objective of this study is to assist in the assessment and interpretation of these cases as well as provide references for confirmation methods. Chemistry, pharmacology, adverse events and user profiles (e.g., polypharmacy) for NPS are provided including case history, clinical symptoms, autopsy findings and analytical results. Literature reviews were performed in PubMed and Google Scholar for publications using search terms such as NPS specific names, general terms (e.g., 'designer drugs' and 'novel psychoactive substances'), drug classes (e.g., 'designer stimulants') and outcome-based terms (e.g., 'overdose' and 'death'). Government and website drug surveillance databases and abstracts published by professional forensic science organizations were also searched. Toxicological data and detailed case information were extracted, tabulated, analyzed and organized by drug category. Case reports included overdose fatalities (378 cases), clinical treatment and hospitalization (771 cases) and driving under the influence of drugs (170 cases) for a total of 1,319 cases providing details of adverse events associated with NPS. Confirmed adverse events with associated toxidromes of more than 60 NPS were reported including synthetic cannabinoid, NPS stimulant, NPS hallucinogen, NPS benzodiazepine and NPS opioid cases. Fifty of these NPS were reported for the first time in January 2017 through December 2020 as compared to the previous 4 years surveyed. This study provides insight and context of case findings described in the literature and in digital government surveillance databases and websites during a recent 4-year period. This review will increase the awareness of adverse events associated with NPS use to better characterize international emerging drug threats.

Phototactic behaviour and neurotransmitter profiles in two Daphnia magna clones: Vertical and horizontal responses to fish kairomones and psychotropic drugs.

Animal behavioural responses are increasingly being used in environmental risk assessment. Nevertheless, behavioural responses are still hampered by a lack of standardisation. Phototactic behaviour in zooplankton and in particular in Daphnia has often been associated to vertical migration but there is also 'shore-avoidance' horizontal behaviour: Daphnia uses shades along the shore to swim either to or away from the shore and predators. Previously, we develop a vertical oriented behavioural hardware able to reproduce phototactic fish induced depth selection in Daphnia magna, its modulation by fish kairomones and psychotropic drugs and the neurotransmitter profiles associated to those responses. This study aims to test if it is possible to use an horizontal 24 multi-well plate maze set up to assess phototactic fish induced responses in D. magna. The study was conducted using two clones with opposed phototaxis upon exposure to fish kairomones and using psychotropic drugs known to modulate phototaxis. Acrylic strips opaque to visible light but not to the infrared one were used to cover half of the arena of each of the wells of the multi-well plate. Clone P132,85 showed positive phototaxis in either the vertical and horizontal set up and negative phototaxis when exposed to fish kairomones or to the muscarinic acetylcholine receptor antagonist's scopolamine and atropine. The opposite behaviour was observed for clone F. Diazepam and pilocarpine ameliorate fish kairomone induced negative phototaxis and picrotoxin increased it only in clone P132,85 in the vertical set up. The determination of neurotransmitters showed much greater concentrations of dopamine and of glycine in clone F, which may be relate to its negative phototaxis and its observed lower responsiveness to fish kairomones. The results from this study suggest a simple, fast, and high throughput phototactic behaviour assay for D. magna that can be easily adapted to other species.

Toxicokinetic evaluation during intoxication of psychotropic drugs using brain microdialysis in mice.

In the event of an overdose, the pharmacokinetics of the drug may be altered, resulting in an unexpectedly rapid increase in blood and tissue drug concentrations. Because central nervous system (CNS)-acting drugs are the major cause of hospitalization for overdose, brain concentrations, which are closely related to the development of acute psychotropic symptoms, would be important. However, due to the lack of an appropriate model for overdose, it is difficult to predict the CNS symptoms of patients with acute poisoning. To clarify the toxicokinetics during intoxication with CNS-acting drugs, we investigated the relationship between the dose and concentrations in the blood and brain in mice. Therapeutic or toxic doses of phenobarbital, flunitrazepam, imipramine, and amoxapine were administered intraperitoneally to mice. Serum and extracellular fluid of the brain were collected up to 24 hr after administration and analyzed using LC-MS/MS to determine the pharmacokinetic parameters in the serum and brain. A comparison of the four psychotropic drugs showed that the toxicokinetics of amoxapine in the blood and brain are clearly different from others, with the brain concentrations being specifically highly susceptible to increase during dose escalation. These results are consistent with the CNS-related symptoms observed in amoxapine overdose. Therefore, the methodology of the current study could be useful for predicting CNS toxicity during psychotropic drug poisoning.

Developments in high-resolution mass spectrometric analyses of new psychoactive substances.

The proliferation of new psychoactive substances (NPS) has necessitated the development and improvement of current practices for the detection and identification of known NPS and newly emerging derivatives. High-resolution mass spectrometry (HRMS) is quickly becoming the industry standard for these analyses due to its ability to be operated in data-independent acquisition (DIA) modes, allowing for the collection of large amounts of data and enabling retrospective data interrogation as new information becomes available. The increasing popularity of HRMS has also prompted the exploration of new ways to screen for NPS, including broad-spectrum wastewater analysis to identify usage trends in the community and metabolomic-based approaches to examine the effects of drugs of abuse on endogenous compounds. In this paper, the novel applications of HRMS techniques to the analysis of NPS is reviewed. In particular, the development of innovative data analysis and interpretation approaches is discussed, including the application of machine learning and molecular networking to toxicological analyses.

Environmental occurrence and ecological risks of psychoactive substances.

Psychoactive substances are ubiquitous in the environment at low concentrations, and tobacco, cannabis, etc. are all widely-existing examples. Given their potent biological activity, psychoactive substances are suspected to be harmful to the environment, and reports of their ecological risks are gradually increasing. Since the 1990s, the investigations into psychoactive substances have made remarkable progress, yet some research fields still need to be modernised. For example, the unification of standardised analytical methods as well as the supplementation of occurrence literature. In addition, a relatively lagging risk evaluation system caused by a lack of toxicity data is particularly in need of improvement. The purpose of this article is to develop a review of current research on psychoactive substances, including analytical methods, distribution in environmental compartments, and ecological risk assessment, as well as to point out deficiencies and development prospects and to offer motivation for enhancing the research level in this field.

2-((2-(4-Iodo-2,5-dimethoxyphenyl)ethylamino)methyl)phenol (25I-NBOH) and 2-(((2-(4-chloro-2,5-dimethoxyphenyl)ethyl)amino)methyl)phenol (25C-NBOH) induce adverse effects on the cardiovascular system.

Two new psychoactive substances (NPSs) classified as phenethylamines, namely 2-((2-(4-Iodo-2,5-dimethoxyphenyl)ethylamino)methyl)phenol (25I-NBOH) and 2-(((2-(4-chloro-2,5-dimethoxyphenyl)ethyl)amino)methyl)phenol (25C-NBOH), are being abused by people seeking recreational hallucinogens. These NPSs may cause serious health problems as their adverse effects are not known in most cases. Therefore, in the present study, we evaluated the cardiotoxicity of 25I-NBOH and 25C-NBOH using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, rat electrocardiography (ECG), Langendorff test, and human ether-a-go-go-related gene (hERG) assay. Furthermore, we analyzed the expression levels of p21 CDC42/RAC1-activated kinase 1 (PAK1), which is known to play various roles in the cardiovascular system. In the MTT assay, treatment with 25I-NBOH or 25C-NBOH dramatically decreased viability of H9c2 cardiomyocytes. Meanwhile, these two compounds significantly increased QT intervals and RR intervals in the rat ECG measurement. 25I-NBOH down-regulated the PAK1 protein expression in rat primary cardiomyocytes as well as H9c2 cells. However, 25C-NBOH had no effect on the PAK1 expression in H9c2 cells. In an in-depth study, 25I-NBOH inhibited potassium channels in the hERG assay, but in ex vivo test, the substance did not affect the left ventricular developed pressure (LVDP) and heart rate of the isolated rat hearts. Taken together, these results suggest that both 25I-NBOH and 25C-NBOH may have adverse cardiovascular effect. Further investigation would be needed to determine which factors mainly influence the relationship between PAK1 expression and cardiotoxicity.

4-Fluoromethamphetamine (4-FMA) induces in vitro hepatotoxicity mediated by CYP2E1, CYP2D6, and CYP3A4 metabolism.

4-Fluoromethamphetamine (4-FMA) is an amphetamine-like psychoactive substance with recognized entactogenic and stimulant effects, but hitherto unclear toxicological mechanisms. Taking into consideration that the vast majority of 4-FMA users consume this substance through oral route, the liver is expected to be highly exposed. The aim of this work was to determine the hepatotoxic potential of 4-FMA using in vitro hepatocellular models: primary rat hepatocytes (PRH), human hepatoma cell lines HepaRG and HepG2, and resorting to concentrations ranging from 37 µM to 30 mM, during a 24-h exposure. EC50 values, estimated from the MTT viability assay data, were 2.21 mM, 5.59 mM and 9.57 mM, for each model, respectively. The most sensitive model, PRH, was then co-exposed to 4-FMA and cytochrome P450 (CYP) inhibitors to investigate the influence of metabolism on the toxicity of 4-FMA. Results show that CYP2E1, CYP3A4 and CYP2D6 have major roles in 4-FMA cytotoxicity. Inhibition of CYP2D6 and CYP3A4 led to left-geared shifts in the concentration-response curves of 4-FMA, hinting at a role of these metabolic enzymes for detoxifying 4-FMA, while CYP2E1 inhibition pointed towards a toxifying role of this enzyme in 4-FMA metabolism at physiologically-relevant concentrations. The drug also destabilised mitochondrial membrane potential and decreased ATP levels, increased the production of reactive oxygen and nitrogen species and compromised thiol antioxidant defences. 4-FMA further affected PRH integrity by interfering with the machinery of apoptosis and necrosis, increasing the activity of initiator and effector caspases, and causing loss of cell membrane integrity. Potential for autophagy was also observed. This research contributes to the growing body of evidence regarding the toxicity of new psychoactive substances, in particular regarding their hepatotoxic effects; the apparent influence of metabolism over the resulting cytotoxicity of 4-FMA shows that there is a substantial degree of unpredictability of the consequences for users that could be independent of the dose.

Withania somnifera (L.) Dunal (Ashwagandha): A comprehensive review on ethnopharmacology, pharmacotherapeutics, biomedicinal and toxicological aspects.

Withania somnifera (L.) Dunal (Solanaceae) has been used as a traditional Rasayana herb for a long time. Traditional uses of this plant indicate its ameliorative properties against a plethora of human medical conditions, viz. hypertension, stress, diabetes, asthma, cancer etc. This review presents a comprehensive summary of the geographical distribution, traditional use, phytochemistry, and pharmacological activities of W. somnifera and its active constituents. In addition, it presents a detailed account of its presence as an active constituent in many commercial preparations with curative properties and health benefits. Clinical studies and toxicological considerations of its extracts and constituents are also elucidated. Comparative analysis of relevant in-vitro, in-vivo, and clinical investigations indicated potent bioactivity of W. somnifera extracts and phytochemicals as anti-cancer, anti-inflammatory, apoptotic, immunomodulatory, antimicrobial, anti-diabetic, hepatoprotective, hypoglycaemic, hypolipidemic, cardio-protective and spermatogenic agents. W. somnifera was found to be especially active against many neurological and psychological conditions like Parkinson's disease, Alzheimer's disease, Huntington's disease, ischemic stroke, sleep deprivation, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, bipolar disorder, anxiety, depression, schizophrenia and obsessive-compulsive disorder. The probable mechanism of action that imparts the pharmacological potential has also been explored. However, in-depth studies are needed on the clinical use of W. somnifera against human diseases. Besides, detailed toxicological analysis is also to be performed for its safe and efficacious use in preclinical and clinical studies and as a health-promoting herb.

Worsening of the Toxic Effects of (±)Cis-4,4'-DMAR Following Its Co-Administration with (±)Trans-4,4'-DMAR: Neuro-Behavioural, Physiological, Immunohistochemical and Metabolic Studies in Mice.

4,4'-Dimethylaminorex (4,4'-DMAR) is a new synthetic stimulant, and only a little information has been made available so far regarding its pharmaco-toxicological effects. The aim of this study was to investigate the effects of the systemic administration of both the single (±)cis (0.1-60 mg/kg) and (±)trans (30 and 60 mg/kg) stereoisomers and their co-administration (e.g., (±)cis at 1, 10 or 60 mg/kg + (±)trans at 30 mg/kg) in mice. Moreover, we investigated the effect of 4,4'-DMAR on the expression of markers of oxidative/nitrosative stress (8-OHdG, iNOS, NT and NOX2), apoptosis (Smac/DIABLO and NF-κB), and heat shock proteins (HSP27, HSP70, HSP90) in the cerebral cortex. Our study demonstrated that the (±)cis stereoisomer dose-dependently induced psychomotor agitation, sweating, salivation, hyperthermia, stimulated aggression, convulsions and death. Conversely, the (±)trans stereoisomer was ineffective whilst the stereoisomers' co-administration resulted in a worsening of the toxic (±)cis stereoisomer effects. This trend of responses was confirmed by immunohistochemical analysis on the cortex. Finally, we investigated the potentially toxic effects of stereoisomer co-administration by studying urinary excretion. The excretion study showed that the (±)trans stereoisomer reduced the metabolism of the (±)cis form and increased its amount in the urine, possibly reflecting its increased plasma levels and, therefore, the worsening of its toxicity.

Human Neuronal Cell Lines as An In Vitro Toxicological Tool for the Evaluation of Novel Psychoactive Substances.

Novel psychoactive substances (NPS) are synthetic substances belonging to diverse groups, designed to mimic the effects of scheduled drugs, resulting in altered toxicity and potency. Up to now, information available on the pharmacology and toxicology of these new substances is very limited, posing a considerable challenge for prevention and treatment. The present in vitro study investigated the possible mechanisms of toxicity of two emerging NPS (i) 4'-methyl-alpha-pyrrolidinoexanophenone (3,4-MDPHP), a synthetic cathinone, and (ii) 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA), a phenethylamine. In addition, to apply our model to the class of synthetic opioids, we evaluated the toxicity of fentanyl, as a reference compound for this group of frequently abused substances. To this aim, the in vitro toxic effects of these three compounds were evaluated in dopaminergic-differentiated SH-SY5Y cells. Following 24 h of exposure, all compounds induced a loss of viability, and oxidative stress in a concentration-dependent manner. 2-Cl-4,5-MDMA activates apoptotic processes, while 3,4-MDPHP elicits cell death by necrosis. Fentanyl triggers cell death through both mechanisms. Increased expression levels of pro-apoptotic Bax and caspase 3 activity were observed following 2-Cl-4,5-MDMA and fentanyl, but not 3,4-MDPHP exposure, confirming the different modes of cell death.

In Vitro and In Vivo Pharmaco-Toxicological Characterization of 1-Cyclohexyl-x-methoxybenzene Derivatives in Mice: Comparison with Tramadol and PCP.

1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.

Impacts of Psychopharmaceuticals on the Neurodevelopment of Aquatic Wildlife: A Call for Increased Knowledge Exchange across Disciplines to Highlight Implications for Human Health.

The global use of psychopharmaceuticals such as antidepressants has been steadily increasing. However, the environmental consequences of increased use are rarely considered by medical professionals. Worldwide monitoring efforts have shown that pharmaceuticals are amongst the multitude of anthropogenic pollutants found in our waterways, where excretion via urine and feces is thought to be the primary mode of pharmaceutical contamination. Despite the lack of clarity surrounding the effects of the unintentional exposure to these chemicals, most notably in babies and in developing fetuses, the US Environmental Protection Agency does not currently regulate any psychopharmaceuticals in drinking water. As the underlying reasons for the increased incidence of mental illness-particularly in young children and adolescents-are poorly understood, the potential effects of unintentional exposure warrant more attention. Thus, although links between environmental contamination and physiological and behavioral changes in wildlife species-most notably in fish-have been used by ecologists and wildlife biologists to drive conservation policy and management practices, we hypothesize that this knowledge may be underutilized by medical professionals. In order to test this hypothesis, we created a hierarchically-organized citation network built around a highly-cited "parent" article to explore connections between aquatic toxicology and medical fields related to neurodevelopment. As suspected, we observed that studies in medical fields such as developmental neuroscience, obstetrics and gynecology, pediatrics, and psychiatry cite very few to no papers in the aquatic sciences. Our results underscore the need for increased transdisciplinary communication and information exchange between the aquatic sciences and medical fields.

Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics.

New psychoactive stimulants and psychedelics continue to play an important role on the illicit new psychoactive substance (NPS) market. Designer stimulants and psychedelics both affect monoaminergic systems, although by different mechanisms. Stimulant NPS primarily interact with monoamine transporters, either as inhibitors or as substrates. Psychedelic NPS most potently interact with serotonergic receptors and mediate their mind-altering effects mainly through agonism at serotonin 5-hydroxytryptamine-2A (5-HT2A) receptors. Rarely, designer stimulants and psychedelics are associated with potentially severe adverse effects. However, due to the high number of emerging NPS, it is not possible to investigate the toxicity of each individual substance in detail. The brain is an organ particularly sensitive to substance-induced toxicity due to its high metabolic activity. In fact, stimulant and psychedelic NPS have been linked to neurological and cognitive impairments. Furthermore, studies using in vitro cell models or rodents indicate a variety of mechanisms that could potentially lead to neurotoxic damage in NPS users. Cytotoxicity, mitochondrial dysfunction, and oxidative stress may potentially contribute to neurotoxicity of stimulant NPS in addition to altered neurochemistry. Serotonin 5-HT2A receptor-mediated toxicity, oxidative stress, and activation of mitochondrial apoptosis pathways could contribute to neurotoxicity of some psychedelic NPS. However, it remains unclear how well the current preclinical data of NPS-induced neurotoxicity translate to humans.

Toxicology of Psychoactive Substances.

A trend in the increasing use of prescription psychoactive drugs (PADs), including antidepressants, antipsychotics, and mood stabilizers, has been reported in the United States and globally. In addition, there has been an increase in the production and usage of illicit PADs and emergence of new psychoactive substances (NPSs) all over the world. PADs pose unique challenges for critical care providers who may encounter toxicology issues due to drug interactions, side effects, or drug overdoses. This article provides a summary of the toxicologic features of commonly used and abused PADs: antidepressants, antipsychotics, mood stabilizers, hallucinogens, NPSs, caffeine, nicotine, and cannabis.

The impact of state cannabis legislation, county-level socioeconomic and dog-level characteristics on reported cannabis poisonings of companion dogs in the USA (2009-2014).

With current trends in cannabis legalization, large efforts are being made to understand the effects of less restricted legislation on human consumption, health, and abuse of these products. Little is known about the effects of cannabis legalization and increased cannabis use on vulnerable populations, such as dogs. The objective of this study was to examine the effects of different state-level cannabis legislation, county-level socioeconomic factors, and dog-level characteristics on dog cannabis poisoning reports to an animal poison control center (APCC). Data were obtained concerning reports of dog poisoning events, county characteristics, and state cannabis legislation from the American Society for the Prevention of Cruelty to Animals' (ASPCA) APCC, the US Census Bureau, and various public policy-oriented and government websites, respectively. A multilevel logistic regression model with random intercepts for county and state was fitted to investigate the associations between the odds of a call to the APCC being related to a dog being poisoned by a cannabis product and the following types of variables: dog characteristics, county-level socioeconomic characteristics, and the type of state-level cannabis legislation. There were significantly higher odds of a call being related to cannabis in states with lower penalties for cannabis use and possession. The odds of these calls were higher in counties with higher income variability, higher percentage of urban population, and among smaller, male, and intact dogs. These calls increased throughout the study period (2009-2014). Reporting of cannabis poisonings were more likely to come from veterinarians than dog owners. Reported dog poisonings due to cannabis appear to be influenced by dog-level and community-level factors. This study may increase awareness to the public, public health, and veterinary communities of the effects of recreational drug use on dog populations. This study highlights the need to educate dog owners about safeguarding cannabis products from vulnerable populations.

Acute toxicity from the synthetic cathinone N-ethylpentylone (ephylone) in the United Kingdom.

INTRODUCTION: Acute toxicity caused by New Psychoactive Substances (NPS) has created a significant burden for Emergency Departments (EDs). Here we report characteristics of people presenting with toxicity after exposure to the synthetic cathinone N-ethylpentylone (NEP). METHODS: Adults presenting to hospital with severe acute toxicity after suspected NPS use were recruited between March 2015 and October 2020. Clinical features were recorded using consistent methodology and biological samples analysed using liquid chromatography-tandem mass-spectrometry. RESULTS: NEP was detected in at least one sample from 9 of 893 patients recruited during the period of study, all presenting between 2016 and 2019 and 8 presenting in southern England. Commonly reported clinical features included tachycardia (6), agitation (6), confusion (6), mydriasis (5), hallucinations (4), acidosis (3) and elevated creatine kinase (3). Co-used drugs, detected in 6 patients, may have contributed to these features, but agitation and hallucinations were also reported in all 3 patients without analytical evidence of co-use. CONCLUSIONS: NEP was detected infrequently in episodes of drug toxicity in the UK between 2016 and 2019, especially in southern England. Clinical characteristics of toxicity are similar to those of other cathinones, although co-use of other drugs is common and may contribute to the features observed.