Characterization of the Neurochemical and Behavioral Effects of the Phenethylamine 2-Cl-4,5-MDMA in Adolescent and Adult Male Rats.

BACKGROUND: The proliferation of novel psychoactive substances (NPS) in the drug market raises concerns about uncertainty on their pharmacological profile and the health hazard linked to their use. Within the category of synthetic stimulant NPS, the phenethylamine 2-Cl-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) has been linked to severe intoxication requiring hospitalization. Thereby, the characterization of its pharmacological profile is urgently warranted. METHODS: By in vivo brain microdialysis in adolescent and adult male rats we investigated the effects of 2-Cl-4,5-MDMA on dopamine (DA) and serotonin (5-HT) neurotransmission in two brain areas critical for the motivational and rewarding properties of drugs, the nucleus accumbens (NAc) shell and the medial prefrontal cortex (mPFC). Moreover, we evaluated the locomotor and stereotyped activity induced by 2-Cl-4,5-MDMA and the emission of 50-kHz ultrasonic vocalizations (USVs) to characterize its affective properties. RESULTS: 2-Cl-4,5-MDMA increased dialysate DA and 5-HT in a dose-, brain area-, and age-dependent manner. Notably, 2-Cl-4,5-MDMA more markedly increased dialysate DA in the NAc shell and mPFC of adult than adolescent rats, while the opposite was observed on dialysate 5-HT in the NAc shell, with adolescent rats being more responsive. Furthermore, 2-Cl-4,5-MDMA stimulated locomotion and stereotyped activity in both adolescent and adult rats, although to a greater extent in adolescents. Finally, 2-Cl-4,5-MDMA did not stimulate the emission of 50-kHz USVs. CONCLUSIONS: This is the first pharmacological characterization of 2-Cl-4,5-MDMA demonstrating that its neurochemical and behavioral effects may differ between adolescence and adulthood. These preclinical data could help understanding the central effects of 2-Cl-4,5-MDMA by increasing awareness on possible health damage in users.

Screening of Astec® CHIRALDEX™ G-PN and LIPODEX™ D gas chromatography columns for enantioseparation of amphetamine derivatives.

Among different substance classes, New Psychoactive Substances (NPS) comprise chiral amphetamines for stimulant and empathic effects. There is little knowledge in terms of clinical studies about possibly different effects of the two enantiomers of novel amphetamine derivatives. For this reason, there is a big demand for enantioseparation method development of this new substance class. Regarding gas chromatography, cyclodextrins proved to be effective for enantioseparation of NPS. In our attempt, an Astec® Chiraldex™ G-PN column containing 2,6-di-O-pentyl-3-propionyl-γ-cyclodextrin and a Lipodex™ D column containing heptakis-(2,6-di-O-pentyl-O-acetyl)-ß-cyclodextrin as chiral selector served as stationary phases in a Shimadzu GCMS-QP2010 SE system. Because of the special coating, maximum temperature is limited to 200 °C isothermal or 220 °C in programmed mode. To ensure detection, trifluoroacetic anhydride (TFAA) was used to increase sample volatility.1 As a result, 35 amphetamines were tested as their TFAA-derivatives. A screening method with a temperature gradient from 140 °C to 200 °C at a heating ramp of 1 °C per minute and final time of 5 min, showed baseline separation for seven and partial separations for 16 trifluoro acetylated amphetamines using the Chiraldex™ G-PN column. Six baseline and nine partial separations were observed with the Lipodex™ D column, respectively.

The use of premixed drugs in commodity packets in the population: prevalence and correlates revealed by the 2018 National Survey of Substance Use in Taiwan.

BACKGROUND: Administering premixed drugs in commodity packets was first reported in Asia in 2015, but there continues to be a dearth of related population-based data. This study aimed at examining (1) the prevalence of drug packet use in the population and (2) the sociodemographic profiles, particularly gender distribution, of drug packet users. METHODS: Data were derived from a survey of 18,626 Taiwanese civilians, aged 12-64 years, using stratified, multi-stage, random sampling in 2018. Participants anonymously completed a computer-assisted self-interview on tablet computers which covered the use and problematic use of illicit drugs/inhalants, prescription drugs and other psychoactive substances, among others. RESULTS: Approximately 1.46% of respondents had a lifetime use of illicit drugs, with drugs in commodity packets (0.18%) being ranked the fifth-most commonly used illicit drugs, higher than nitrous oxide (0.14%) and heroin (0.09%). Ten formats of drug packets were endorsed by users. Approximately 81.6% of persons with drug packet use had a lifetime use of other illicit drugs. The correlates of the use of drugs in commodity packets were similar to those of the exclusive use of other drugs except that there was a lack of gender differences in the use of drugs in commodity packets but not in the exclusive use of other drugs. CONCLUSION: Drugs in commodity packets have become a common way of administering illicit drugs in the population in Taiwan, and there were no gender differences among users. Our findings have implications for more efficient drug testing and culturally appropriate intervention for drug packet use.

Behavioral and Pharmacokinetics Studies of N-Methyl-2-Aminoindane (NM2AI) in Mice: An Aminoindane Briefly Used in the Illicit Drug Market.

Drug forums are considered as the main platform sources that have contributed to the increase in NPS popularity, especially for those not yet known to law enforcement and therefore not yet illegal. An example is the new synthetic stimulant NM2AI, which has a very short history of human use and abuse. Little is known regarding this compound, but some information from internet forums and the scientific literature indicates NM2AI as a structural derivate of MDAI, which is known for its entactogenic activity. Indeed, the purpose of this study is to evaluate, for the first time, the in vivo acute effect induced by the intraperitoneal injection of NM2AI (1-10-30-100 mg/kg) in mice. We demonstrate the sensory (by visual placing and object tests) and physiological (core temperature measurement) function variations, nociceptor (by tail pinch test) and strength (grip test) alterations, and sensorimotor (time on rod and mobility) decrease. Moreover, we verify the mild hallucinogenic effect of NM2AI (by startle/prepulse inhibition test). Lastly, we perform a pharmacokinetic study on mice blood samples, highlighting that the main active metabolite of NM2AI is 2-aminoindane (2AI). Taken together, our data confirm the suspected entactogenic activity of NM2AI; however, these in vivo effects appear atypical and less intense with respect to those induced by the classic stimulants, in surprising analogy with what is reported by networked users.

Genotoxicity Evaluation of The Novel Psychoactive Substance MTTA.

MTTA, also known as mephtetramine, is a stimulant novel psychoactive substance characterized by a simil-cathinonic structure. To date, little has been studied on its pharmaco-toxicological profile, and its genotoxic potential has never been assessed. In order to fill this gap, the aim of the present work was to evaluate its genotoxicity on TK6 cells in terms of its ability to induce structural and numerical chromosomal aberrations by means of a cytofluorimetric protocol of the "In Vitro Mammalian Cell Micronucleus (MN) test". To consider the in vitro effects of both the parental compound and the related metabolites, TK6 cells were treated with MTTA in the absence or presence of an exogenous metabolic activation system (S9 mix) for a short-term time (3 h) followed by a recovery period (23 h). No statistically significant increase in the MNi frequency was detected. Specifically, in the presence of S9 mix, only a slight increasing trend was observable at all tested concentrations, whereas, without S9 mix, at 75 µM, almost a doubling of the negative control was reached. For the purposes of comprehensive evaluation, a long-term treatment (26 h) was also included. In this case, a statistically significant enhancement in the MNi frequency was observed at 50 µM.

Human Astrocyte Spheroids as Suitable In Vitro Screening Model to Evaluate Synthetic Cannabinoid MAM2201-Induced Effects on CNS.

There is growing concern about the consumption of synthetic cannabinoids (SCs), one of the largest groups of new psychoactive substances, its consequence on human health (general population and workers), and the continuous placing of new SCs on the market. Although drug-induced alterations in neuronal function remain an essential component for theories of drug addiction, accumulating evidence indicates the important role of activated astrocytes, whose essential and pleiotropic role in brain physiology and pathology is well recognized. The study aims to clarify the mechanisms of neurotoxicity induced by one of the most potent SCs, named MAM-2201 (a naphthoyl-indole derivative), by applying a novel three-dimensional (3D) cell culture model, mimicking the physiological and biochemical properties of brain tissues better than traditional two-dimensional in vitro systems. Specifically, human astrocyte spheroids, generated from the D384 astrocyte cell line, were treated with different MAM-2201 concentrations (1-30 µM) and exposure times (24-48 h). MAM-2201 affected, in a concentration- and time-dependent manner, the cell growth and viability, size and morphological structure, E-cadherin and extracellular matrix, CB1-receptors, glial fibrillary acidic protein, and caspase-3/7 activity. The findings demonstrate MAM-2201-induced cytotoxicity to astrocyte spheroids, and support the use of this human 3D cell-based model as species-specific in vitro tool suitable for the evaluation of neurotoxicity induced by other SCs.

Toxicological and pharmacological characterization of novel cinnamylpiperazine synthetic opioids in humans and in vitro including 2-methyl AP-237 and AP-238.

The recent scheduling actions of fentanyl-related substances in both the United States and China have sparked the emergence and proliferation of other generations of "legal" opioids that are structurally distinct from fentanyl, including the recently emerged class of cinnamylpiperazines. In contrast to fentanyl, which contains a piperidine core and a phenethyl moiety, the primary structural components of cinnamylpiperazines are the piperazine core and a cinnamyl moiety. This manuscript reports on the toxicological profile for antemortem and postmortem cases where a cinnamylpiperazine was detected. Samples were quantitatively confirmed using liquid chromatography tandem mass spectrometry. The cases were received between February 2020 and April 2021. Concentrations of 2-methyl AP-237 from four postmortem cases ranged from 820 to 5800 ng/mL, and concentrations of AP-238 from two postmortem cases were 87 and 120 ng/mL. µ-Opioid receptor (MOR) activation potential for 2-methyl AP-237, AP-237, para-methyl AP-237, and AP-238 were studied using a ßarr2 recruitment assay. Efficacies (Emax, relative to hydromorphone) and potencies (EC50) were derived and of the compounds tested AP-238 was the most potent compound in the panel with an EC50 of 248 nM. 2-Methyl AP-237 was found to be the most efficacious drug (Emax = 125%) of the tested cinnamylpiperazines; however, it had substantially less efficacy than fentanyl. The in vitro MOR activation potential of the studied cinnamylpiperazines was lower than that of fentanyl and other novel synthetic opioids (NSOs), in line with the relatively higher concentrations observed in postmortem toxicology samples-an important observational link between in vitro pharmacology and in vivo toxicology.

Pharmacokinetics, systemic toxicity, thermoregulation and acute behavioural effects of 25CN-NBOMe.

N-(2-methoxybenzyl)phenethylamines (NBOMes) are a family of potent 5-HT2A agonists containing substances emerging on the illicit drug market as a replacement for N,N-diethyllysergamide (LSD). Despite the increasing use of NBOMes for diagnostic, research and recreational purposes, only a limited number of studies have focussed on their in vivo effect. Here, we investigated pharmacokinetics, systemic toxicity, thermoregulation in individually and group-housed animals, and acute behavioural effects after subcutaneous administration of 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe; 0.2, 1, and 5 mg/kg) in Wistar rats. Drug concentration peaked 1 h after the administration of 5 mg/kg in both blood serum and brain tissue with a half-life of 1.88 and 2.28 h, respectively. According to Organisation for Economic Co-operation and Development 423 toxicity assay, the drug is classified into category 3 with a lethal dose of 300 mg/kg and an estimated LD50 value of 200 mg/kg. Histological examination of organs collected from rats injected with the lethal dose revealed subtle pathological changes, highly suggestive of acute cardiovascular arrest due to malignant arrhythmia. Altered thermoregulation after 5 mg/kg was demonstrated by reduced body temperature in individually housed rats (p < 0.01). Behavioural effects assessed by the Open Field test and Prepulse Inhibition of Startle Response revealed that the two lower doses (0.2 and 1 mg/kg) caused a reduction in locomotor activity (p < 0.01), increased anxiety (p < 0.05) and 5 mg/kg additionally impaired sensorimotor gating (p < 0.001). In summary, 25CN-NBOMe readily passes the blood-brain barrier and exhibits a moderate level of toxicity and behavioural effect comparable with other NBOMes.

Genotoxicological Characterization of (±)cis-4,4'-DMAR and (±)trans-4,4'-DMAR and Their Association.

The novel psychoactive substance (NPS) 4-Methyl-5-(4-methylphenyl)-4,5-dihydroxazol-2-amine (4,4'-DMAR) shows psychostimulant activity. Data on the acute toxicity of 4,4'-DMAR are becoming increasingly available, yet the long-term effects are still almost unknown. In particular, no data on genotoxicity are available. Therefore, the aim of the present study was to evaluate its genotoxic potential using the "In Vitro Mammalian Cell Micronucleus Test" (MNvit) on (±)cis-4,4'-DMAR and (±)trans-4,4'-DMAR and their associations. The analyses were conducted in vitro on human TK6 cells. To select suitable concentrations for MNvit, we preliminarily evaluated cytotoxicity and apoptosis. All endpoints were analysed by flow cytometry. The results reveal the two racemates' opposite behaviours: (±)cis-4,4'-DMAR shows a statistically significant increase in micronuclei (MNi) frequency that (±)trans-4,4'-DMAR is completely incapable of. This contrast confirms the well-known possibility of observing opposite biological effects of the cis- and trans- isomers of a compound, and it highlights the importance of testing single NPSs that show even small differences in structure or conformation. The genotoxic capacity demonstrated stresses an additional alarming toxicological concern related to this NPS. Moreover, the co-treatments indicate that consuming both racemates will magnify the genotoxic effect, an aspect to consider given the unpredictability of illicit drug composition.

Designer benzodiazepines versus prescription benzodiazepines: can structural relation predict the next step?

Designer benzodiazepines are a part of the recently discovered abuse synthetic drugs called Novel Psychoactive Substances (NPS) which need to be controlled due to their constantly growing market. Most of them are derived from the medically approved benzodiazepines used nowadays yet, may possess stronger effects, more toxicity, and longer durations of action. Some differences have also been observed in their detection and characteristics, in addition to the variations discovered in postmortem redistribution and drug stability. All these major alterations in features can result from only minor structural modifications. For example, a classic benzodiazepine (BZD) like diazepam only lacks one fluorine atom which exists in its derivatized designer drug, diclazepam, making substantial differences in activity. For this reason, it is essential to study the designer drugs in order to identify their dangers and distinguish them thus rule out their abuse and control the spread of such drugs. This review would highlight the distinct characteristics of some of the most commonly abused designer benzodiazepine analogies in relation to their original prescription BZD compounds.

Substance-related exogenous psychosis: a postmodern syndrome.

There is growing recognition that substance use is associated with the emergence of psychosis.Elements of post-modernity dominate contemporary social contexts and operate as existential background factors that contribute to the emergence of substance-related psychotic phenomena, particularly use of potent and highly rewarding novel psychoactive substances (NPS). About 25% of first-episode psychoses are substance-induced (SIP). DSM-5 SIP diagnosis is based on the assumption that symptoms are transient and disappear after sustained abstinence. This narrowed definition does not consider the issue of persistent SIP. There is a clear need for a new diagnostic framework that provides reliable, unambiguous clinical criteria to differentiate between comorbid conditions (i.e., schizophrenia patients with a substance use disorder) and substance-related psychoses. In the present contribution, we aim to outline a novel and separate clinical entity: substancerelated exogenous psychosis (SREP). Within this diagnostic category, we refer to both transientand persistent psychoses associated with substance use. SREP is conceived as a distinct psychoticdisorder with psychopathological specificities that clearly differentiate it from schizophrenia. We address differences in terms of clinical presentation, epidemiology, etiological models and treatment response. SREP is characterized by altered states of consciousness, persecutory delusions, visual and cenesthetic hallucinations, impulsivity and psychomotor agitation, affectiveand negative symptoms, a pervasive feeling of unreality and intact insight. Delusions are typically secondary to abnormal perception resulting from a characteristic "sensorialization" of the world. Longitudinal studies are warranted to substantiate our hypothesis of a novel diagnostic categoryand support the clinical validity of SREP. This may have important implications in terms of early differential diagnosis and staging (i.e., between comorbid conditions, persistent and transientsubstance-related psychotic states) as well as choice of treatment interventions.

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.

Evaluation of Cytotoxic and Mutagenic Effects of the Synthetic Cathinones Mexedrone, α-PVP and α-PHP.

Mexedrone, α-PVP and α-PHP are synthetic cathinones. They can be considered amphetamine-like substances with a stimulating effect. Actually, studies showing their impact on DNA are totally absent. Therefore, in order to fill this gap, aim of the present work was to evaluate their mutagenicity on TK6 cells. On the basis of cytotoxicity and cytostasis results, we selected the concentrations (35-100 µM) to be used in the further analysis. We used the micronucleus (MN) as indicator of genetic damage and analyzed the MNi frequency fold increase by flow cytometry. Mexedrone demonstrated its mutagenic potential contrary to the other two compounds; we then proceeded by repeating the analyzes in the presence of extrinsic metabolic activation in order to check if it was possible to totally exclude the mutagenic capacity for α-PVP and α-PHP. The results demonstrated instead the mutagenicity of their metabolites. We then evaluated reactive oxygen species (ROS) induction as a possible mechanism at the basis of the highlighted effects but the results did not show a statistically significant increase in ROS levels for any of the tested substances. Anyway, our outcomes emphasize the importance of mutagenicity evaluation for a complete assessment of the risk associated with synthetic cathinones exposure.

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.

Understanding the UK Psychoactive Substances Act.

This review paper is based on a talk given at the British Pharmaceutical Society Winter Meeting in 2018 derived from the Home Office Report on the workings of the UK Psychoactive Substances Act (PSA) published in November 2018. The review deals with the context in which the PSA 2016 arose and how this piece of legislation differs from other UK drug regulations. It attempts to put the PSA in context with other control schemes being instituted around the world and to assess the success of the Act in its first 2 years of implementation. For more details the reader is referred to Review of the Psychoactive Substances Act 2016, Home Office, November 2018.

How deaths can help clinicians and policy-makers understand the risks of novel psychoactive substances.

Novel psychoactive substances (NPS), especially those newly created, are largely an unknown quantity, particularly in terms of their potential serious adverse effects. This means that policy-makers and clinicians are under-informed about appropriate responses. Collation of detailed information on deaths related to NPS use can help in providing knowledge and understanding these aspects of the NPS phenomenon. The purpose of this review is to outline the role(s) which such evidence-based data can play in this respect. UK NPS-related cases demonstrate differences in definitions used by the General Mortality Registers, and differences between countries, not only in terms of the type of NPS implicated in deaths, but the number and extent of such deaths over time. NPS deaths are continuing to increase numerically and as a proportion of all drug-poisoning deaths. In order to better understand how specific molecules contribute to and/or cause death, detailed information collected by Special Mortality Registers can provide examples of substances' modes of action, adverse effects, symptomatology, treatment interventions, mechanisms of death, etc. This information can provide clinicians and policy-makers with objective information on the serious harms from such emerging molecules. Such evidence-based advice informs public health interventions, service provision and policy decisions on regulation and control of NPS. However, without reliable, accurate and complete information that is correctly collated, scientifically analysed and disseminated in a timely manner, an understanding of the phenomenon of what deaths can be ascribed to NPS, their characteristics and nature will remain unachieved, and thus limit what can be done to reduce them.

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

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

Methiopropamine and its acute behavioral effects in mice: is there a gray zone in new psychoactive substances users?

Methiopropamine is a structural analog of methamphetamine that is categorized as a novel psychoactive substance. It primarily acts as a norepinephrine-dopamine reuptake inhibitor and, secondarily, as a serotonin reuptake inhibitor. In humans, methiopropamine induces stimulation and alertness and increases focus and energy. However, significant side effects are reported, such as tachycardia, anxiety, panic attacks, perspiration, headache, and difficulty in breathing. To date, little data is available regarding its pharmacodynamic effects, thereby we aimed to investigate the acute in vivo effects induced by this drug on sensorimotor responses, body temperature, pain thresholds, motor activity, and cardiovascular and respiratory systems in CD-1 male mice. We selected a range of doses that correspond to the whole range of human reported use, in order to evaluate the threshold of adverse effects presentation. This study demonstrates that methiopropamine acts as a dopaminergic and noradrenergic stimulating drug and that the highest doses (10-30 mg/kg) impair the visual placing response, facilitate the acoustic and tactile response, induce hypothermia, increase mechanical and thermal analgesia, stimulate locomotor activity, induce motor stereotypies, and strongly affected cardiovascular and respiratory parameters, increasing heart rate, breath rate, and blood pressure but reducing oxygen saturation. On the contrary, lower doses do not show any of those effects. We hypothesize that there is a range of doses that do enhance performance but do not seem hazardous to users: this gap could induce the perception of safety and increase the abuser population.

Determination of the chiral status of different novel psychoactive substance classes by capillary electrophoresis and ß-cyclodextrin derivatives.

Besides the abuse of well-known illicit drugs, consumers discovered new synthetic compounds with similar effects but minor alterations in their chemical structure. Originally, these so-called novel psychoactive substances (NPS) have been created to circumvent law of prosecution because of illicit drug abuse. During the past decade, such compounds came up in generations, the most popular compound was a synthetic cathinone derivative named mephedrone. Cathinones are structurally related to amphetamines; to date, more than 120 completely new derivatives have been synthesized and are traded via the Internet. Cathinones possess a chiral center; however, only little is known about the pharmacology of their enantiomers. However, NPS comprise further chiral compound classes such as amphetamine derivatives, ketamines, 2-(aminopropyl)benzofurans, and phenidines. In continuation of our project, a cheap and easy-to-perform chiral capillary zone electrophoresis method for enantioseparation of cathinones presented previously was extended to the aforementioned compound classes. Enantioresolution was achieved by simply adding native ß-cyclodextrin, acetyl-ß-cyclodextrin, 2-hydroxypropyl-ß-cyclodextrin, or carboxymethyl-ß-cyclodextrin as chiral selector additives to the background electrolyte. Fifty-one chiral NPS served as analytes mainly purchased from online vendors via the Internet. Using 10 mM of the aforementioned ß-cyclodextrins in a 10 mM sodium phosphate buffer (pH 2.5), overall, 50 of 51 NPS were resolved. However, chiral separation ability of the selectors differed depending on the analyte. Additionally, simultaneous enantioseparations, the determination of enantiomeric migration orders of selected analytes, and a repeatability study were performed successfully. It was proven that all separated NPS were traded as racemic mixtures.

Phenotypic effects of chronic and acute use of methiopropamine in a mouse model.

Methiopropamine (MPA) is a structural analogue of methamphetamine and belongs to the category of the novel psychoactive substances. To the best of our knowledge, no experimental study has been performed to evaluate the organ damage evoked by MPA administration in an animal model. Therefore, the main purpose of the present study was to investigate the histological changes in CD-1 male mice following the chronic administration of MPA. MPA-chronically treated mice showed myocardial damage with features consistent with repeated episodes of ischemia and a pattern of kidney damage and gastrointestinal ischemia, with ischemic-necrotic lesions of variable extent. In agreement with the analogies between MPA and methamphetamine, we link organ damage secondary to MPA administration to the vasoconstrictive effect exhibited by both compounds. Chronically MPA-treated mice did not show changes in body weight, food intake, thermoregulation, muscular strength and motor coordination in the accelerod test. However, acute MPA administration significantly increased their heart rate and promoted vasoconstriction, which were associated with the sudden death of a subset of animals (40% of all chronically treated mice). In conclusion, the present study demonstrates that MPA consumption could induce health hazards, highlighting the risk of sudden catastrophic events; therefore, clinicians should be aware of these data and consider MPA screening when no other drug is identified by a urine drug screen.