ArticleLiterature Review

The Toxicology of Bath Salts: A Review of Synthetic Cathinones

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Abstract

Synthetic cathinones have recently emerged and grown to be popular drugs of abuse. Their dramatic increase has resulted in part from sensationalized media attention as well as widespread availability on the Internet. They are often considered "legal highs" and sold as "bath salts" or "plant food" and labeled "not for human consumption" to circumvent drug abuse legislation. Cathinone is a naturally occurring beta-ketone amphetamine analogue found in the leaves of the Catha edulis plant. Synthetic cathinones are derivatives of this compound. Those that are being used as drugs of abuse include butylone, dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, mephedrone, methedrone, methylenedioxypyrovalerone (MDPV), methylone, and pyrovalerone. Synthetic cathinones are phenylalkylamines derivatives, and are often termed "bk-amphetamines" for the beta-ketone moiety. They may possess both amphetamine-like properties and the ability to modulate serotonin, causing distinct psychoactive effects. Desired effects reported by users of synthetic cathinones include increased energy, empathy, openness, and increased libido. Cardiac, psychiatric, and neurological signs and symptoms are the most common adverse effects reported in synthetic cathinone users who require medical care. Deaths associated with use of these compounds have been reported. Exposure to and use of synthetic cathinones are becoming increasingly popular despite a lack of scientific research and understanding of the potential harms of these substances. The clinical similarities to amphetamines and MDMA specifically are predictable based on the chemical structure of this class of agents. More work is necessary to understand the mechanisms of action, toxicokinetics, toxicodynamics, metabolism, clinical and psychological effects as well as the potential for addiction and withdrawal of these agents.

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... The observation of synthetic cathinones' effects on CNS led to the study of their pharmacology and, eventually, their medical application to treat depression, chronic fatigue and obesity [73,74]. Otherwise, synthetic cathinones have also been used by undiagnosed attention-deficit/hyperactivity disorder (ADHD) adolescents, who self-medicate with synthetic cathinones [75]. ...
... Synthetic cathinones, namely methcathinone and bupropion, might be used in the treatment of depression. Methcathinone was used as an antidepressant in the 1930s and 1940s, and bupropion is still prescribed for the treatment of depression and smoking cessation by the FDA [73,81]. ...
... Fatal cases related to the consumption of synthetic cathinones have been reported. However, many of these cases are associated with exposition to synthetic cathinones concomitantly with other drugs of abuse [45,73,244]. In this section, reported fatal toxicity cases after exposition to synthetic cathinones, therapeutically used, are addressed. ...
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Background: Novel psychoactive substances (NPS) are compounds of natural and synthetic origin, similar to traditional drugs of abuse. NPS are involved in a contemporary trend whose origin lies in a thinner balance between legitimate therapeutic drug research and legislative control. The contemporary NPS trend resulted from the replacement of MDMA by synthetic cathinones in 'ecstasy' during the 2000s. The most common NPS are synthetic cannabinoids and synthetic cathinones. Interestingly, during the last 50 years, these two classes of NPS have been the object of scientific research for a set of health conditions. Methods: Searches were conducted in the online database PubMed using boolean equations. Results: Synthetic cannabinoids displayed protective and therapeutic effects for inflammatory, neurodegenerative and oncologic pathologies, activating the immune system and reducing inflammation. Synthetic cathinones act similarly to amphetamine-type stimulants and can be used for depression and chronic fatigue. Conclusions: Despite the scientific advances in this field of research, pharmacological application of NPS is being jeopardized by fatalities associated with their recreational use. This review addresses the scientific achievements of these two classes of NPS and the toxicological data, ending with a reflection on Illicit and NPS control frames.
... Intramuscular and subcutaneous (s.c.) injection, rectal insertion ("booty bumping" or "plugging"), gingival and sublingual delivery, inhalation (vaporization/smoking through e-cigarettes) and insertion of the substance into the eyes ("eyeballing") were also reported, although being less common routes (Gonçalves et al. 2019; Karila and Benyamina 2018;Papaseit et al. 2017;Riley et al. 2020). Of note, multiple simultaneous routes of administration have been reported for a single session (Karila and Benyamina 2018;Prosser and Nelson 2012). Additionally, SCs are usually abused concomitantly with several other substances, either intentionally [e.g. in a context of a "chemsex" party, in which mephedrone has been reported to be abused in addition to methamphetamine (METH) and/or 4-hydroxybutanoic acid (GHB) or its precursor oxolan-2-one (GBL), to facilitate, sustain and Table 4 IUPAC names, common names, and chemical structures of 3,4-methylenedioxy-N-pyrrolidine synthetic cathinones (colour figure online) ...
... Typically, the doses of SCs vary largely, from a few milligrams to a couple of grams. It depends on the derivative of choice and on the route of administration, as well as on the uncertainty of the "bath salt" content, namely the present substances, their concentrations and purity, which can often not correspond to the vendor's marketing claims and lead to higher probability of onset of unwanted effects or even overdosing (Brandt et al. 2011;Davies et al. 2010;Kelly 2011;Paillet-Loilier et al. 2014;Prosser and Nelson 2012;Zawilska and Wojcieszak 2018). According to user reports, the typical "single-use" oral doses for MDPV and mephedrone differ significantly, ranging from 2 to 25 mg and from 15 to 300 mg, respectively (Erowid 2015a, b). ...
... According to some surveys, mephedrone abusers typically use between 0.5 and 1.9 g (divided into multiple "single-use" doses which are administered over time) per single session, that can last an average of 9-10 h, or even longer periods (24-48 h) (Carhart-Harris et al. 2011;Jones et al. 2016;Kapitány-Fövény et al. 2013;Lea et al. 2011;Newcombe 2009;Winstock et al. 2011b). Regarding SC nasal insufflation, it is generally characterized by a more rapid onset of the desired effects and lower doses are required to attain those effects, when compared to the oral ingestion (Gonçalves et al. 2019;Kelly 2011;Prosser and Nelson 2012;Valente et al. 2014). As it will be discussed below, the bioavailability of SCs largely varies between 7 and 11% for 3-methylmethcathinone (3-MMC) (Shimshoni et al. 2015) and mephedrone , and ranges from 78 to 89% for methylone . ...
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Cathinone, the main psychoactive compound found in the plant Catha edulis Forsk. (khat), is a β-keto analogue of amphetamine, sharing not only the phenethylamine structure, but also the amphetamine-like stimulant effects. Synthetic cathinones are derivatives of the naturally occurring cathinone that largely entered the recreational drug market at the end of 2000s. The former “legal status”, impressive marketing strategies and their commercial availability, either in the so-called “smartshops” or via the Internet, prompted their large spread, contributing to their increasing popularity in the following years. As their popularity increased, the risks posed for public health became clear, with several reports of intoxications and deaths involving these substances appearing both in the social media and scientific literature. The regulatory measures introduced thereafter to halt these trending drugs of abuse have proved to be of low impact, as a continuous emergence of new non-controlled derivatives keep appearing to replace those prohibited. Users resort to synthetic cathinones due to their psychostimulant properties but are often unaware of the dangers they may incur when using these substances. Therefore, studies aimed at unveiling the pharmacological and toxicological properties of these substances are imperative, as they will provide increased expertise to the clinicians that face this problem on a daily basis. The present work provides a comprehensive review on history and legal status, chemistry, pharmacokinetics, pharmacodynamics, adverse effects and lethality in humans, as well as on the current knowledge of the neurotoxic mechanisms of synthetic cathinones.
... Methylone, also known as MDMC, M1, and bk-MDMA, is a ring-substitute β-keto analogue of the well-known 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) [6]. Since its first appearance as a "room odorizer" in smartshops, methylone gained popularity as a substitute for the traditional MDMA [7]. ...
... Among the published cases of intoxication involving methylone [27][28][29][30][31][32], a patient that visited the emergency department after using 1.0-1.5 g of methylone presented vomiting, palpitations, agitation, sweating, paresthesia, muscle twitching, tremors, and vertigo [33]. Other adverse effects associated with methylone intoxication are hyperthermia, anxiety, seizures, psychosis, hallucinations, and suicidal ideation [6]. ...
Article
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Considered the β-keto analogue of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), 3,4-Methylenedioxymethcathinone (methylone) is a synthetic cathinone. Over the years, methylone has been used as a substitute for conventional psychostimulants, such as MDMA. To date, little is known about the human pharmacology of methylone; the only available information has been provided by surveys or published intoxication reports. In the present observational–naturalistic study, we evaluate the acute subjective and physiological effects of methylone after oral self-administration in comparison to MDMA in healthy poly-drug users. Fourteen participants (10 males, 4 females) selected their single oral doses of methylone from 100 to 300 mg (n = 8, mean dose 187.5 mg) or MDMA from 75 to 100 mg (n = 6, mean dose 87.5 mg) based on their experience. Study variables were assessed at 0, 1, 2, and 4 h (h) and included vital signs (non-invasive blood pressure, heart rate, cutaneous temperature) and subjective effects using visual analogue scales (VAS), the 49-item Addiction Research Centre Inventory (ARCI) short form, and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) questionnaire. Additionally, oral fluid concentrations of methylone and MDMA were determined. Acute pharmacological effects produced by methylone followed the prototypical psychostimulant and empathogenic profile associated with MDMA, although they were less intense. Methylone concentrations in oral fluid can be considered a useful biomarker to detect acute exposure in oral fluid. Oral fluid concentrations of MDMA and methylone peaked at 2 h and concentrations of MDMA were in the range of those previously described in controlled studies. Our results demonstrate that the potential abuse liability of methylone is similar to that of MDMA in recreational subjects.
... Cathinone and its synthetic derivatives exhibit structures similar to those of amphetamines, differing through the attachment of a ketone to the beta position of the amino alkyl chain on the phenyl ring (Prosser & Nelson, 2012), and are therefore referred to as β-keto amphetamines (Zaitsu et al., 2011). Cathinone, methcathinone (B) (A) 10 and methylone, for example, are the β-keto analogues of amphetamine, methamphetamine and MDMA, respectively ( Fig. 1.5). ...
... Whilst variant degrees of agitation are a frequent symptom indicative of recent usage of a number of designer drugs (Weaver et al., 2015), anxiety is often cited as an adverse effect of NPS (Sande, 2016) and synthetic cathinones (Prosser & Nelson, 2012;Assi et al., 2017), and has been reported by mephedrone users as the most common of all adverse effects (Carhart-Harris et al., 2011). Such is the frequency of this effect, that reports of anxiety are indicated to be significantly more prevalent in recreational users of mephedrone than of MDMA . ...
Article
Mephedrone (4-methylmethcathinone) is an illicit psychoactive stimulant and synthetic cathinone which gained prominence in the UK as a “legal high” circa 2008, subsequently being made illegal following media reports of adverse effects and links to several fatalities, as well as its structural similarity to amphetamine. Today, mephedrone remains in recreational use worldwide, often consumed alongside traditional illicit substances such as methamphetamine and gamma-hydroxybutyrate (GHB), or legal drugs such as caffeine and alcohol. In rats, co-administration of caffeine with MDMA (3,4-methylenedioxymephampethamine), has been shown to potentiate the elevation of extracellular 5-HT brain levels, a neurochemical correlate of the serotonin syndrome. In humans, this syndrome is characterised by adverse physiological effects including fever, agitation and hypertension. Despite increased elucidation of its pharmacological profile since 2008, there remains a paucity of data on mephedrone’s behavioural and neurochemical effects, particularly when combined with caffeine. The present thesis sought to somewhat mitigate this deficit. First, a repeated dosing regimen was designed to assess the acute effects of repeated mephedrone administration, with and without caffeine, on behavioural and physiological measures in adolescent rats, and any lasting changes in anxiety, cognition and microglial activation in adulthood. Second, following the observation of hyperthermia and stereotyped behaviours in adolescent rats, an in vivo microdialysis study was designed to elucidate whether this apparent serotonin syndrome was elicited via increased downstream activation of postsynaptic 5-HT1A receptors by endogenous 5-HT. In sum, mephedrone elicited changes in body temperature and locomotor hyperactivity in both studies (with tolerance to the latter developing throughout the one-week binge-type dosing period in study 1). In each case, caffeine converted mephedrone-induced hypothermia to hyperthermia, and enhanced mephedrone-induced stereotyped behaviours. Pre-administration of the 5-HT1A receptor antagonist WAY-100,635 failed to prevent any of these effects, and in fact sped the onset of the hyperthermic response, perhaps via downstream effects following binding to 5-HT1A autoreceptors in the dorsal raphe nuclei. Nonetheless, no lasting effects of mephedrone, caffeine, or the combination of each, were observed on recognition memory, anxiety, sensorimotor gating, conditioned freezing or hippocampal microglial activation.
... SCat can be found on the market in products sold as "bath salts" or "plant feeders", in different forms, including tablets, capsules, crystals or powders [1,9]. These substances are usually taken orally, either by swallowing capsules or 'bombing', where the powder is wrapped in a cigarette paper and subsequently swallowed [10,11]. Inhalation is another common mode of administration of these substances, whereas gingival delivery, intravenous or intramuscular injection and rectal administration are less common routes [11,12]. ...
... Similarly to other stimulant drugs like cocaine or 3,4-methylenedioxymethamphetamine (MDMA), SCat interact with monoamine membrane transporters, leading to an increase in serotonin concentrations (5-HT), dopamine (DA) and noradrenaline (NA) [8,10,13]. In general, these substances create a feeling of euphoria, alertness, empathy, and increased libido, being highly sought after as an alternative to traditional drugs of abuse [14,15]. ...
Article
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The innovation of the new psychoactive substances (NPS) market requires the rapid identification of new substances that can be a risk to public health, in order to reduce the damage from their use. Twelve seized products suspected to contain illicit substances were analyzed by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), gas chromatography coupled to mass spectrometry (GC-MS), and nuclear magnetic resonance spectroscopy (NMR). Synthetic cathinones (SCat) were found in all products, either as a single component or in mixtures. Infrared spectra of all products were consistent with the molecular structure of SCat, showing an intense absorption band at 1700-1674 cm −1 , corresponding to the carbonyl stretching, a me-dium/strong peak at 1605-1580 cm −1 , indicating stretching vibrations in the aromatic ring (C=C) and bands with relative low intensity at frequencies near 2700-2400 cm −1 , corresponding to an amine salt. It was possible to identify a total of eight cathinone derivatives by GC-MS and NMR analysis: 4'-methyl-α-pyrrolidinohexanophenone (MPHP), α-pyrrolidinohexanophenone (α-PHP), 3-fluoro-methcathinone (3-FMC), methedrone, methylone, buphedrone, N-ethylcathinone, and pentedrone. Among the adulterants found in these samples, caffeine was the most frequently detected substance , followed by ethylphenidate. These results highlight the prevalence of SCat in seized materials of the Portuguese market. Reference standards are usually required for confirmation, but when reference materials are not available, the combination of complementary techniques is fundamental for a rapid and an unequivocal identification of such substances.
... One such hazard is the increased risk of drug-related toxicity. Serious, and sometimes fatal events may occur due to the replacement of a drug of low potency and toxicity for a more potent or toxic one (Prosser & Nelson, 2012;Stevens et al., 2015). Substitution could also be considered a form of concurrent polydrug use, in which PWUD consume more than one drug in a given time-period (Karjalainen et al., 2017;Martin et al., 1992). ...
... Other reasons appear to only play a marginal role in motivating substitution. Substitution to avoid the legal consequences associated with the use of a preferred substance ("legal consequences") was a commonly cited motivation of substitution with NPS in previous studies (Brandt et al., 2014;Prosser & Nelson, 2012). In this study, less than 3% of the patients surveyed cited "legal consequences" as a motivation for substituting. ...
Article
Background: Self-substitution is the conscious switch from one drug to another for reasons such as price, availability, desired effect, or perceived benefit of the substitute drug. Purpose/Objectives: This study aimed to describe drug use patterns and motivations associated with substitution. We examined correlates of lifetime substitution among individuals with substance use disorder. Methods: A cross-sectional study of 771 treatment-enrolled individuals. We used self-report for determining the lifetime prevalence, correlates, and motivations for substitution. Results: Of the 771 respondents, 570 (73.9%) reported ever substituting their preferred substance. The main incentives for substitution were availability (23.7%) and curiosity (20.2%). Among heroin or cannabis preferers, improved effects or less adverse effects of the substitute drug, self-medication, and managing withdrawal symptoms were significant substitution incentives. Increased odds for substitution were observed for past 12 months use of cannabis (OR = 1.51, CI = 1.06-4.52), prescription opioids (OR = 2.86, CI = 1.81-4.52), novel psychoactive substances (OR = 2.68, CI = 1.64-4.36), and repeated admission (OR = 1.50, CI = 1.05-2.14). Older age at onset-of-use was negatively associated with substitution (OR = 0.95, CI = 0.93-0.98). Conclusions: Self-substitution of one substance for another is a highly prevalent behavior among treatment-enrolled patients with substance use disorder. Clinicians caring for substance use disorder patients should be aware of substitution patterns involving the use of highly potent substances, which constitutes a risk to patients. Results underscore the benefit of substitution patterns analyses, as they reveal important information on the characteristics of persons who use drugs and their motivations.
... Nevertheless, future studies to reduce the needed volume of whole blood are encouraged.Since the legislation on NPS is based on a substance-by substance (individual listing) basis or on generic or analogue control, rather than on define biological concentrations,40 literature data on previous NPS analytical methods and on intoxications were used to establish the linearity ranges of the present study and to verify whether the sensitivity was acceptable. According to the literature, SCAs and stimulants in blood tend to be quantified mostly at few dozen/hundred nanograms per milliliter after recreational use and even higher levels are to be expected in cases of acute toxicity.11,12,22,41,42 Tryptamines, fentanyl and SOs are also typically characterized by high concentrations in post-mortem or intoxication samples,13,24,43,44 while expected concentrations of SCs in blood are generally lower.13,14,[44][45][46] ...
Article
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Introduction: The analysis of novel psychoactive substances (NPS) represents a challenge in forensic toxicology, due to the high number of compounds characterized by different structures and physicochemical properties both among different subclasses and within a single subclass of NPS. The aim of the present work is the development and validation of a targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the detection of NPS in whole blood. Materials and methods: A protein-precipitation based LC-MS/MS method for the detection of more than 180 NPS was developed and validated by assessing the following parameters: selectivity, linearity, accuracy, precision, limit of detection (LOD) and of quantification (LOQ) recovery and matrix effect. Then, the method was applied to real forensic samples. Results: The method allowed the identification of 132 synthetic cannabinoids, 22 synthetic opioids, as well as 28 substances among synthetic cathinones, stimulants and other drugs. Validation was successfully achieved for most of the compounds. Linearity was in the range of 0.25-10 ng/mL for synthetic cannabinoids and 0.25-25 ng/mL for other drugs. Accuracy and precision were acceptable according to international guidelines. Three cases tested positive for fentanyl and ketamine, in the setting of emergency room administration. Conclusions: The present methodology represents a fast, not expensive, wide-panel method for the analysis of more than 180 NPS by LC-MS/MS, which can be profitably applied both in a clinical context and in postmortem toxicology.
... Synthetic cathinones, including butylone, ethylone, mephedrone, methedrone, 3,4methylenedioxypyrovalerone (MDPV) and methylone are all derived from methcathinone [196,197]. Mephedrone impaired working memory [198], verbal learning, verbal fluency, cognitive flexibility [199] and spatial memory [200] in users. Research show that adult rats would show impairments in spatial memory and reversal learning after repeated mephedrone exposure in adolescence and mephedrone would induce more deleterious effects on cognition than amphetamine due to GluN2B-containing N-methyl-D-aspartate (NMDA) receptor dominance [201] while exposure to mephedrone during gestation induced an impairment of spatial learning and reference memory in offspring [202]. ...
Article
Psychoactive substances are a class of chemical substances which could cause public health threats. Cognitive disorders are a category of mental health disorders that primarily affect cognitive abilities. Tau protein could maintain neuronal cytoskeleton stabilization. Post-translational modification of tau, especially phosphorylation, is an important way to regulate the structure and function of tau and phosphorylated tau is closely related to cognitive function. Lots of studies have reported the phenomenon that psychoactive substances can cause cognitive function impairment. We reviewed recent related studies and discussed them by drug classification. We mainly focused on cognitive disorders caused by acute or chronic exposure of each drugs, animal experiments and the mechanisms associated with tau phosphorylation, then compared the similarities and differences among them, trying to find out the common rules. The results suggested that tau phosphorylation is involved in psychoactive substance-induced cognitive disorder and different psychoactive substances may act by affecting amount or activity of different kinases and phosphatases in the metabolic pathway of tau. We demonstrated that tau protein is a potential target for psychoactive substances induced cognitive disorder treatments.
... Other designer drugs like "Bath salts", which have similar effects to cocaine, induce acute intraparenchymal and subarachnoid haemorrhage as well as ischemic infarction [227]. Bath salt intoxication in a 36-year-old man led to delayed encephalopathy, dysautonomia, fulminant hepatic failure, and renal failure from severe rhabdomyolysis [228], and in a 14-year-old girl, this was accompanied by hyponatremia [229]. ...
Article
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Synthetic Cannabinoids (CBs) are a novel class of psychoactive substances that have rapidly evolved around the world with the addition of diverse structural modifications to existing molecules which produce new structural analogues that can be associated with serious adverse health effects. Synthetic CBs represent the largest class of drugs detected by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) with a total of 207 substances identified from 2008 to October 2020, and 9 compounds being reported for the first time. Synthetic CBs are sprayed on natural harmless herbs with an aim to mimic the euphoric effect of Cannabis. They are sold under different brand names including Black mamba, spice, K2, Bombay Blue, etc. As these synthetic CBs act as full agonists at the CB receptors, they are much more potent than natural Cannabis and have been increasingly associated with acute to chronic intoxications and death. Due to their potential toxicity and abuse, the US government has listed some synthetic CBs under schedule 1 classification. The present review aims to provide a focused overview of the literature concerning the development of synthetic CBs, their abuse, and potential toxicological effects including renal toxicity, respiratory depression, hyperemesis syndrome, cardiovascular effects, and a range of effects on brain function.
... The main distribution channels for these substances are now online shops, where they can be purchased under various names, e.g. 'Flakka', 'Vanilla Sky', 'Cherry Cocolino', 'Ivory Wave', or so-called 'research chemicals' (3,4). ...
Article
Synthetic cathinones (SCs) are currently the second largest and the second most frequently seized group of new psychoactive substances. They are sold as replacements for controlled stimulants such as amphetamine, cocaine and MDMA. Administration of low doses of SCs can cause euphoria and increased alertness, and administration of high doses or chronic use of cathinones can cause serious adverse effects, such as hallucinations, delirium, hyperthermia, and tachycardia. In the years 2013-2019 in our practice, as many as 16 different SCs were detected in biological materials. Presented article lists the observed concentrations in 39 fatal and 18 non-fatal cases, in which a single SC as well as an SC in combination with amphetamine or ethyl alcohol were detected and quantified in biological materials. The quantitative analyses were carried out by LC-MS/MS. The analysed cases of taking SCs were associated with intoxication (2 cases), fatal intoxication (36), driving under the influence of drugs (10), and other circumstances (9), such as violence, insulting an officer, and holding a hostage. Taking SCs has serious side effects that can lead to multiple organ failure and death. Screening for the presence of SCs in biological materials should be part of the routine course of treatment in intoxication cases, both at the stage of clinical diagnosis and at the stage of forensic toxicological analysis. Ethyl alcohol and amphetamine may contribute to increased SC toxicity. This data could be valuable for further interpretation of other results from toxicological analyses.
... 1 Similarly, the toxic effects include increased blood pressure (BP), tachycardia, insomnia, anorexia, constipation, general malaise, irritability, migraine, and impaired sexual potency in men. 3 Cathinone, the main stimulant in khat, is shown to be associated with cardiovascular and neurological toxicity. [10][11][12] It has vasoconstrictor activity that leads to high BP. 13 Thus, its effect on BP might be related to the increased incidence of acute myocardial infarction (AMI) that occurs during the khat-effective period and is associated with heavy khat chewing. ...
Article
Khat ( Catha edulis ) chewing is linked to several social, psychological, and health-related problems. Studies show that khat is associated with gastrointestinal and nervous system diseases. However, little is known about khat’s effect on the cardiovascular system. This case report describes acute myocardial infarction (AMI) among two young adults who chew khat frequently, but who do not have underlying cardiovascular disease (CVD) risk factors. Case 1 is a 29-year-old apparently healthy man who presented with severe, squeezing, left-side chest pain after consumption of khat. Most of the laboratory results were within the normal range except for his serum troponin level, which was 400 times more than the normal limit. The patient was diagnosed with Killip class IV, ST-segment elevation, anteroseptal AMI. Case 2 is a 25-year-old man who is a frequent khat chewer. He presented with sudden-onset, severe, squeezing, retrosternal chest pain after khat chewing and vigorous activity. The patient was diagnosed with (Killip class III) acute ST-elevation myocardial infarction with cardiogenic pulmonary edema. These case reports describe two young adult male patients who were confirmed of having AMI with no known risk factors. Both cases had a similar history of frequent khat chewing and the onset of AMI after it, implying that khat could be an important CVD risk factor among young adults. Hence, it is essential to explore further the epidemiology and association between khat use and AMI. Both molecular and population-level studies could help to establish the causal relationship of khat and CVD.
... Chemsex is defined as the use of drugs during sexual activity in order to enhance the performance, duration or pleasure (Bourne et al., 2014;Giorgetti et al., 2017). These practices have been increasing among men having sex with men (MSM) for the past 10 years, appearing as an emerging public health phenomenon (Prosser & Nelson, 2012). In the 2017 European MSM Internet Survey (The EMIS Network, 2019), 15.2% of the respondents reported having ever practiced chemsex, 10.4% during the last 12 months, and 5.2% in the last 4 weeks. ...
Article
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ContextChemsex involves mental and sexual health risks for users, which generate specific needs in primary care. The aim of this study is to evaluate the role of the general practitioner (GP) in the identification of disorders and first aid offered to MSM chemsex users (CUs).Methods Data were collected with a self-administered questionnaire offered to MSM patients consulting in six Parisian STI clinics. The primary endpoint was the number of GP visits reported by patients in the past 12 months between CUs and control.ResultsThree hundred sixty-four MSMs were included between October and December of 2018: 94 CUs (25.9%) and 270 control. The multivariate analysis showed no statistically significant difference in the number of GP visits in the past 12 months (3.27 vs 2.66, p = 0.205). CUs had a higher number of sexual partners (p < 0.001) and used PrEP more often (OR 3.33 [CI95% 1.81–6.22]). Among the CUs, 67% had consulted their GP for STI testing in the last 12 months and 29.7% for PrEP. About 28.3% had ever mentioned their chemsex practices at GP and 10.9% had taken sick leaves at least once.Conclusion Our study explored the impact of chemsex on the demand for care at GP. There is an association of chemsex with PrEP.Policy ImplicationsThe relays of PrEP and chemsex care in general practice in the coming years require an awareness from health professionals. The management of chemsex complications should be extended into care networks and include GPs.
... The rise in core body temperature is a typical and life-threatening side effect of amphetamine's abuse in humans (Prosser & Nelson, 2012;da Silva et al., 2014). Thus, we monitored the changes in body temperature during NEP chronic exposure at a dose of 10 mg/kg, using a rectal probe. ...
Article
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N‐ethyl‐pentylone (NEP), also known as “ephylone” and N‐ethylnorpentylone, has been identified as one of the most recent novel psychostimulants to emerge into the illicit drug market and it has been associated with some intoxications and even fatalities. However, little is known about the consequences of its repeated consumption as well as the role of the monoaminergic system in such consequences. Thus, the aim of our study was to investigate the neurochemical profile and the behavioural effects after both acute and repeated NEP exposure. Male OF1 mice were acutely (1, 3, 10 mg/kg, i.p.) or repeatedly (1, 3, 10 mg/kg, i.p., 5 days, twice/day) exposed to NEP, and anxiety‐like behaviour, aggressiveness, social interaction, depressive‐like symptoms, body temperature, changes in monoaminergic enzymes and neurotransmitters levels as well as ΔFosB in striatum and prefrontal cortex (PFC) from post‐mortem tissue were analysed short after drug‐exposure or during drug‐withdrawal. Acute administration of NEP induced anxiolytic effects but also an aggressive behaviour and social exploration deficits in mice, which persist during NEP‐withdrawal. Moreover, NEP induced hyperthermia as well as depressive‐like symptoms after repeated administrations that may be related to the decrease of serotonin and noradrenaline levels observed in striatum and PFC. Finally, the long‐term increase in ΔFosB levels in striatum after NEP chronic exposure points to a high risk of dependence. Altogether indicates that NEP consumption induces different neurological and neuropsychiatric disorders accompanied by changes in the monoaminergic system, posing a threat to public health.
... The number of synthetic cannabinoids is still on the rise in many countries worldwide. This class of compounds is a class of analogs that mimic the traditional drug Δ 9 -tetrahydrocannabinol (THC), which is highly addictive, inexpensive, easy to conceal, and difficult to detect [1][2][3][4]. It is often used as a substitute for traditional drugs. ...
Article
In recent years, an increasing number of new synthetic cannabinoids have appeared on the drug trade market. Many of the new synthetic cannabinoids have not previously been reported. At present, there are relatively few methods available for detecting synthetic cannabinoids and their metabolites in hair matrices. Therefore, we established a simple and fast method to simultaneously identify 29 synthetic cannabinoids and their metabolites in human hair by UPLC-MS/MS. Twenty milligrams of hair was used and processed by cryo-grinding and extraction with methanol. A Waters Acquity UPLC HSS T3 column (100 mm × 2.1 mm, 1.8 μm) was used for chromatographic separation. Mobile phase A was comprised of 20 mmol/L ammonium acetate, 0.1% formic acid, and 5% acetonitrile and water, and mobile phase B was acetonitrile. The method was fully validated and proved to have good selectivity, accuracy, precision, and satisfactory linearity within the calibrated range. The limit of detection (LOD) ranged from 0.5 to 5 pg/mg, and the lower limit of quantitation (LLOQ) ranged from 1–10 pg/mg. The extraction recovery was 36.1-93.3%, and the matrix effect was 19.1-110.0%. The validated method was successfully used to qualitatively and quantitatively analyze 29 synthetic cannabinoids and their metabolites in 59 actual hair samples. MDMB-4en-PINACA had the highest positive detection rate followed by ADB-BUTINACA, and there are multiple synthetic cannabinoid mixed ingestions. This methodology has great potential for the detection of 29 synthetic cannabinoids and their metabolites in forensic cases.
... Given that NPS are commercialized as "legal" substitutes for illegal recreational drugs, there is a perception that these are less dangerous, and individuals may consume them thinking they are not merely legal, but also medically safe [12,13]. Nevertheless, these new drugs can produce strong psychoactive effects, acute intoxication, and serious medical complications, such as seizures, strokes, cardiovascular toxicity, renal failure, hyperthermia, respiratory depression, loss of consciousness, delirium, psychosis, and many others [1,3,[14][15][16]. Furthermore, NPS have the potential to produce strong withdrawal syndromes, tolerance, and addiction [17][18][19], and they are related to an increased risk of developing severe infectious diseases, such as HIV and HCV [20,21]. ...
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This study aims to determine prevalence and frequency of use of novel psychoactive substances (NPS) and to identify the factors associated with NPS use in an Italian sample of patients diagnosed with substance use disorder (SUD). Prevalence and correlates of NPS knowledge and use were assessed in 185 patients with SUD in three addiction services (Padova, Belluno, Feltre) in the Veneto region with an ad-hoc designed survey. Two thirds of the samples reported knowing NPS and one third reported using them. NPS were considered by them less dangerous than “regular” substances of abuse (t = 6.06 mean 0.78, p < 0.001). Factors associated with NPS use were youth (OR = 4.81; p < 0.001), studentship (OR = 4.99; p = 0.004), subsequent mental disorders diagnosis (OR = 2.49; p = 0.027), suicide attempt history (OR = 11.67; p < 0.001), home detention (OR = 2.30; p = 0.040), residential care (OR = 5.66; p = 0.002), and polysubstance abuse (t = 8.99 mean 2.65 p < 0.001). NPS use in patients with SUD is highly prevalent, particularly in the youngest age group, and associated with psychiatric comorbidity and worse prognosis. It is crucial to systematically assess NPS use and inform addiction service users with SUD of the toxic and potentially lethal side effects. Mental healthcare professionals working in addiction services should receive education and training. Cohort and longitudinal studies are needed.
... Due to the similarity in structure to amphetamine and amphetamine derivatives, cathinone is widely used for its stimulant effects [4]. Cathinone has served as a template drug for the synthesis of a wide range of novel and very potent synthetic cathinones (SCt), such as mephedrone, methcathinone and methylone, which also exhibit amphetamine-like effects [4,5]. Information about the toxic effects of SCt and their detection in biological matrices (e.g., urine and blood) does not reach the scientific community as quickly as they emerge on the market due to the straightforward production and subsequent availability of numerous analogues with similar substituents. ...
Article
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The use of illicit drugs is exceedingly prevalent in society, and several of them can be illegally purchased from the internet. This occurrence is particularly augmented by the rapid emergence of novel psychoactive substances (NPS), which are sold and distributed as “legal highs”. Amongst NPS, the class of synthetic cathinones represents stimulant substances exhibiting similar effects to amphetamine and its derivatives. Despite potentially being less psychoactive than amphetamine, synthetic cathinones are harmful substances for humans, and little or no information is available regarding their pharmacology and toxicology. The present study investigated the in vitro metabolism and metabolites of four recent synthetic cathinones, namely, 1-(4-methylphenyl)-2-(methylamino)-pentanone (4-MPD), 1-(4-methylphenyl)-2-dimethylamino-propanone (2-NMC), 1-(4-fluorophenyl)-2-(pyrrolidin-1-yl-hexanone (4F-PHP) and 1-(1,3-benzodioxol-5-yl)-2-(ethylamino)-1-pentanone (bk-EPDP). Our in vitro metabolism study resulted in 24 identified metabolites, including both phase I and phase II metabolites. All metabolites were detected and identified using liquid chromatography–high-resolution mass spectrometry and may serve as additional markers of abuse of these NPS in toxicological analyses.
... It has been shown that some of these substances are extensively more potent than their analogues. Several cases of acute toxicity and deaths have been already reported to this novel class of compounds [2][3][4]. NPS are mostly sold on the internet or in so-called 'head shops' as 'plant food', 'bath salts' or as 'research chemicals' and are strictly marked 'not for human consumption' [5]. ...
Article
Hair samples are frequently analyzed in order to characterize consumption patterns of drugs. However, the interpretation of new psychoactive substance (NPS) findings in hair remains difficult because of lacking data for comparison. In this study, selected postmortem hair samples (n = 1203) from 2008 to 2020 were reanalyzed for synthetic cathinones, piperazines, phenethylamines, hallucinogens, benzodiazepines and opioids to evaluate prevalence data and concentration ranges. Hair samples were extracted using a two‐step extraction procedure and analyzed using a validated liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method. Overall new psychoactive substances were detected in 381 cases (31.6 %). Many cases were tested positive for more than one NPS in the same time span. A variety of NPS with a large range of concentrations was observed. For better comparability and interpretation of positive cases in routine work, quantitation data for 13 NPS were calculated as percentiles. The most frequently detected NPS in this study were N‐ethylamphetamine, α‐pyrrolidinovalerophenone, mephedrone, benzedrone, metamfepramone and 4‐fluoroamphetamine. In conclusion, a high prevalence of these drugs was observed from postmortem hair samples. The results show a growing use of many different NPS by mainly young drug‐using adults. Consequently, NPS screening procedures should be included in forensic toxicology. Our quantitative data may support other toxicologists in their assessment of NPS hair concentrations.
... Taking cathinones may also induce symptoms of serotonin syndrome with disorders of the central nervous system, autonomic nervous system instability and neuromuscular hyperactivity. This risk increases with the use of additional psychoactive substances, such as cocaine and amphetamine (85)(86)(87). The article has been published recently in which the authors maintain that Serotonin Syndrome (SS) may be related to overactivation of the serotoninergic system produced by several mechanisms resulting in a classic triad of altered mental status, neuromuscular effects, and autonomic hyperactivity. ...
Article
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Background: In recent years, an increase in the frequency of hospitalizations of patients taking newer and newer psychoactive substances has been observed around the world. Each year, authors publish case reports of patients who consumed previously unknown NPS. Most publications of this type concern the period between 2014 and 2016. However, no publication systematically reviews the pharmacotherapy used in these cases. This study aims to review the case reports of patients taking NPS published between 2010 and 2019, as well as analyzing the pharmacotherapy used. Methods: We searched the Thomson (Web of Knowledge), PubMed/Medline, Science Direct, Scopus and Google Scholar databases. The search was performed using all possible combinations of the term “case report” describing the use of NPS, also referred to as designer medications, internet medications, research chemicals and herbal highs. Results: We analyzed 51 case reports on the intake of various types of NPS. Most of them ( p < 0.001) concerned the use of synthetic cannabinoids (41.2%) and cathinones (31.4%). The pharmacotherapy applied primarily ( p < 0.001) consisted of administering benzodiazepines to patients (62.7%), most of whom took only this group of medications (25.5%), followed by groups receiving benzodiazepines combined with neuroleptics (15.7%) and muscle relaxants (11.8%). Opioids were administered primarily to patients taking synthetic opioids ( p < 0.001). Of the 5 cases of deaths from NPS reported in the literature, three relate specifically to the synthetic opioid MT-45. The later the time period, the more medications patients were administered ( p = 0.02). Conclusion: In the pharmacotherapy for NPS poisoning, one should focus primarily on combating psychomotor agitation.
... Además de la peligrosidad inherente al consumo abusivo propiamente dicho, el riesgo se incrementa por el hecho de utilizarse varios fármacos de forma conjunta, en muchas ocasiones mezclados con alcohol u otras drogas (Burillo-Putze et al., 2012). En este sentido, se ha observado entre jóvenes estadounidenses el uso del denominado "trail mix", consistente en reuniones en las que cada asistente recolecta fármacos del botiquín de su casa, mezclándolos luego en un recipiente, para consumirlos de forma aleatoria (Prosser y Nelson, 2012). Otro aspecto para tener en cuenta con el pharming es la posibilidad de que sirva como puerta de entrada al consumo de otras drogas ilegales, como ocurre con el "cheese", mezcla de heroína con antigripales (fundamentalmente difenhidramina y acetaminofén), que causa euforia y alucinaciones tras inhalarlo y que es conocida como la "heroína de inicio" (Maxwell, Coleman, Feng, Goto y Tirado, 2012). ...
... Cathinones are used as cheap substitutes for other central stimulants, such as amphetamines or cocaine. Although the chemical structure of cathinones is similar to that observed in the structure of amphetamines, synthetic cathinones possess distinct psychopharmacological properties [5]. The structure of β-keto-amphetamine gives cathinones similar but not identical effects to amphetamine. ...
Article
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Nowadays, more and more young people want to experience illegal, psychoactive substances, without knowing the risks of exposure. Besides affecting social life, psychoactive substances also have an important effect on consumer health. We summarized and analyzed the published literature data with reference to the mechanism of free radical generation and the link between chemical structure and oxidative stress related to dopaminergic neurotransmission. This review presents data on the physicochemical properties, on the ability to cross the blood brain barrier, the chemical structure activity relationship (SAR), and possible mechanisms by which neuronal injuries occur due to oxidative stress as a result of drug abuse such as “bath salts”, amphetamines, or cocaine. The mechanisms of action of ingested compounds or their metabolites involve intermediate steps in which free radicals are generated. The brain is strongly affected by the consumption of such substances, facilitating the induction of neurodegenerative diseases. It can be concluded that neurotoxicity is associated with drug abuse. Dependence and oxidative stress are linked to inhibition of neurogenesis and the onset of neuronal death. Understanding the pathological mechanisms following oxidative attack can be a starting point in the development of new therapeutic targets.
... However, along with all these effects, some other negative effects have also been reported by users. Since these compounds are simultaneously consumed with other drugs and their users might sometimes be clueless about which drug they have taken, it might be hard to relate the effects directly to synthetic cathinones [53]. Misunderstanding of the potency of these drugs can result in death, with overdose and suicide being the two most common causes (due to the psychological effects of the drug, such as loss of impulse control) [54]. ...
Article
New psychoactive substances represent a public health threat since they are not controlled by international conventions, are easily accessible online and are sold as a legal alternative to illicit drugs. Among them, synthetic cathinones are widely abused due to their stimulant and hallucinogenic effects. To circumvent the law, new derivatives are clandestinely synthesized and, therefore, synthetic cathinones keep emerging on the drug market, with their chemical and toxicological properties still unknown. In this review, a literature assessment about synthetic cathinones is presented focusing on the recent developments, which include more than 50 derivatives since 2014. A summary of their toxicokinetic and toxicodynamic properties are also presented. Furthermore, synthetic cathinones are chiral compounds, meaning that they can exist as two enantiomeric forms which may present different biological and toxicological activities. To analyze the enantiomers, the development of enantiomeric resolution methods for synthetic cathinones is crucial. Many methods have been reported over the years that include mostly chromatographic and electromigration techniques, with liquid chromatography using chiral stationary phases being the technique of choice. This review intended to present an overview of enantioselectivity studies and enantioseparation analysis regarding synthetic cathinones, highlighting the relevance of chirality and current trends.
... Cathinones are used as cheap substitutes for other central stimulants, such as amphetamines or cocaine. Although the chemical structure of cathinones is similar to that observed in the structure of amphetamines, synthetic cathinones possess distinct psychopharmacological properties [5]. The structure of β-keto-amphetamine gives cathinones similar but not identical effects to amphetamine. ...
... Amphetamine derivatives can induce increases in core body temperature which, reaching a certain extent, can become a life-threatening side effect (Da Silva et al., 2014;Prosser and Nelson, 2012). As this effect has also been reported for cathinones, we monitored the changes in body temperature during NEPD chronic exposure at the dose of 10 mg/kg. ...
Article
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N-ethyl-pentedrone (NEPD, 2-(ethylamino)-1-phenyl-1-pentanone) is one of the latest synthetic cathinone derivatives that emerged into the illicit drug market. This drug has psychostimulant properties and has been related with several intoxications and even fatalities. However, information about the consequences of its acute and repeated consumption is lacking. Thus, the aim of our study was to investigate the behavioral effects after both acute and repeated NEPD exposure as well as the neurochemical changes. Male OF1 mice were treated with an acute dose (1, 3 or 10 mg/kg, i.p.) or received repeated injections of these doses (twice/day, 5 days) of NEPD. Shortly after drug-exposure or during drug-withdrawal, anxiety-like behavior, aggressiveness, social interaction, depressive-like symptoms, body weight and temperature were assessed. Also, monoamine synthesis enzymes, levels of neurotransmitters and their precursors and main metabolites, as well as ΔFosB, were determined in striatum and prefrontal cortex from post-mortem tissue. Acute administration of NEPD induced anxiolytic effects and reduced social exploration whereas during withdrawal after repeated administration the anxiolytic effect had vanished, and the reduced social exploration was still present and accompanied with increased aggressive behavior. Moreover, NEPD (10 mg/kg) induced slight hyperthermia and reduced weight gain during the repeated administration, whereas increased locomotor activity and lack of depressive symptoms were found during withdrawal. This was accompanied by increased plasma corticosterone and decrease in striatal dopamine. Finally, the long-lasting and robust increase in ΔFosB levels found in striatum after NEPD chronic exposure suggests a high risk of dependence. The increased aggressivity and locomotor activity, together with this potential of inducing dependence justify a warning about the risks of consumption of NEPD if translated to humans.
... We did not find previous reports of ischemic strokes caused by α-PVP, although cardiovascular events such as myocardial infarction had been previously reported [3]. Structurally and pharmacologically synthetic cathinones are similar to amphetamine, and physiological changes include hypertension, arrythmia, and vasoconstriction, which are known to cause strokes [5]. ...
Article
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Alpha-pyrrolidinovalerophenone (α-PVP) is a designer drug, the mechanism of action of which resembles that of cocaine and amphetamine. New data about the side effects of α-PVP are emerging. We present a case report of an acute ischemic stroke following the recreational use of α-PVP. The ischemic lesions were located in the middle cerebral artery and deep watershed areas of the left cerebral hemisphere. Occupational therapy and physiotherapy were initiated, and the patient was discharged with only a mild right hemiparesis.
Article
In recent years, the consumption of synthetic cathinones has grown continuously as these drugs represent a more affordable and obtainable alternative to amphetamines. After consumption, cathinones have a stimulant effect and can be found in the human organism in their pure form or metabolized. As these compounds are difficult to monitor by routine drug screening it is very important to develop procedures capable of detecting and monitoring their consumption. Different strategies have been developed for the analysis of cathinones in biological matrices such as blood, hair or oral fluid. However, urine has been most widely used as the procedure is non-invasive and samples can be obtained in larger volumes than other biological matrices. The present review provides a critical discussion of the latest trends for the determination of cathinones in urine samples, focusing particularly on the use of chromatographic techniques, which is the approach most widely reported in the literature.
Article
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The emergence of new psychoactive drugs in the market demands rapid and accurate tools for the on‐site classification of illegal and legal compounds with similar structures. Herein, a novel method for the classification of synthetic cathinones (SC) is presented based on their electrochemical profile. First, the electrochemical profile of five common SC (i.e., mephedrone, ethcathinone, methylone, butylone and 4‐chloro‐alpha‐pyrrolidinovalerophenone) is collected to build calibration curves using square wave voltammetry on graphite screen‐printed electrodes (SPE). Second, the elucidation of the oxidation pathways, obtained by liquid chromatography‐high resolution mass spectrometry, allows the pairing of the oxidation products to the SC electrochemical profile, providing a selective and robust classification. Additionally, the effect of common adulterants and illicit drugs on the electrochemical profile of the SC is explored. Interestingly, a cathodic pretreatment of the SPE allows the selective detection of each SC in presence of electroactive adulterants. Finally, the electrochemical approach is validated with gas‐chromatography‐mass spectrometry by analyzing 26 confiscated samples from seizures and illegal webshops. Overall, the electrochemical method exhibits a successful classification of SC including structural derivatives, a crucial attribute in an ever‐diversifying drug market.
Chapter
Exposure to pharmaceutical, occupational, or environmental toxins may cause or increase the risk of certain neurological emergencies. Early identification of the exposure and the toxin can be instrumental in the diagnosis and management of toxin-induced neurological emergencies. This chapter reviews the toxins associated with hyperthermic syndromes, ischemic and hemorrhagic stroke, seizures and status epilepticus, weakness, and acute encephalopathy.
Chapter
Recreational drug use has shifted from primarily illicit substances to an increasing number of prescription medications. Neurologic complications of these substances include disorders of the central and peripheral nervous system and range from mild agitation, as is seen in some patients when intoxicated with methamphetamines, to life-threatening intracerebral hemorrhage from cocaine intoxication or the toxic leukoencephalopathy resulting from inhaled vaporized opiates. In addition, there is increasing recognition that chronic abuse of some of these substances can lead to long-term neurologic and psychiatric sequelae. New substances are constantly emerging and clinicians need to stay up-to-date and vigilant regarding their neurologic manifestations.
Article
Cathinone derivatives are the most representative group within new drugs market, which have been described as neurotoxic. Since cathinones, as pentedrone and methylone, are available as racemates, it is our aim to study the induced neuronal cytotoxicity by each enantiomer. Therefore, a dopaminergic SH-SY5Y cell line was used to evaluate the hypothesis of enantioselectivity of pentedrone and methylone enantiomers on cytotoxicity, oxidative stress, and membrane efflux transport (confirmed by in silico studies). Our study demonstrated enantioselectivity of these cathinones, being the S-(+)-pentedrone and R-(+)-methylone the most oxidative enantiomers and also the most cytotoxic, suggesting the oxidative stress as main cytotoxic mechanism, as previously described in in vitro studies. Additionally, the efflux transporter multidrug resistance associated protein 1 (MRP1) seems to play, together with GSH, a selective protective role against the cytotoxicity induced by R-(−)-pentedrone enantiomer. It was also observed an enantioselectivity in the binding to P-glycoprotein (P-gp), another efflux protein, being the R-(−)-pentedrone and S-(−)-methylone the most transported enantiomeric compounds. These results were confirmed, in silico, by docking studies, revealing that R-(−)-pentedrone is the enantiomer with highest affinity to MRP1 and S-(−)-methylone and R-(−)-pentedrone are the enantiomers with highest affinity to P-gp. In conclusion, our data demonstrated that pentedrone and methylone present enantioselectivity in their cytotoxicity, which seems to involve, different oxidative reactivity as well as different affinity to the P-gp and MRP1 that together with GSH, play a protective role.
Article
Background and Objectives Approximately 10 years ago, “bath salts” became popular as legal alternatives to the psychostimulants cocaine and the amphetamines. These products contained synthetic cathinones, including 3,4-methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4-methylenedioxymethcathinone (methylone). Most preclinical investigations have only assessed the effects of these synthetic cathinones independently; however, case reports and Drug Enforcement Administration (DEA) studies indicate that bath salts contain mixtures of these substances. In this study, we examine the pharmacokinetic interactions of the drug combination. We hypothesized that combined exposure to MDPV, mephedrone, and methylone would result in increased drug concentrations and enhanced total drug concentrations when compared to individual administration.Methods Adolescent male Swiss–Webster mice were injected intraperitoneally with either 10 mg/kg MDPV, 10 mg/kg mephedrone, 10 mg/kg methylone, or 10 mg/kg combined MDPV, mephedrone, and methylone. Following injection, brains and plasma were collected at 1, 10, 15, 30, 60, and 120 min. Drugs were extracted via solid-phase extraction, and concentrations were determined using a previously published high-pressure liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) method.ResultsAll drugs crossed the blood–brain barrier quickly. For methylone, the maximal concentration (Cmax) and the total drug exposure [as represented by the area under the concentration-time curve (AUC)] were significantly higher when combined with mephedrone and MDPV in both matrices (2.89-fold increase for both Cmax and AUC with combined treatment). For mephedrone, the Cmax was unchanged, but the AUC in brain was increased when in combination by approximately 34%. Interestingly, for MDPV, the Cmax was unchanged, yet the AUC was higher when MDPV was administered individually (there was a 62% decrease in AUC with combined treatment).Conclusions The pharmacokinetics of methylone, mepedrone, and MDPV are altered when the drugs are used in combination. These data provide insight into the consequences of co-exposure to synthetic cathinones in popular bath salt products.
Article
Mephedrone is a commonly abused drug, with recreational users comparing its effects to MDMA. Polydrug use of mephedrone has been widely documented and forensic analysis has identified caffeine as key drug that is co-consumed. The current study aimed to identify the changes in c-fos expression, a commonly used marker in research to determine neuronal stimulation in response to mephedrone and caffeine administration, and the effect that inhibition of the 5-HT1A receptor has on this expression. 48 male Lister Hooded rats received i.p. vehicle (saline 1mL/kg) or WAY-100635 (0.5mg/kg) then 30min later vehicle, caffeine (10mg/kg), mephedrone (10mg/kg) or caffeine plus mephedrone (10mg/kg each). Animals were killed using Euthatal and brains were removed to determine c-Fos expression. (This in vivo work was performed by a previous PhD student). Free-floating sections cut coronally at 60μm, and immunohistochemistry was performed. Mephedrone displayed a main effect in the dorsal striatum, pre-limbic cortex, the nucleus accumbens core and shell. In the shell, the post-hoc tests showed a significant difference between the vehicle + vehicle treatment group and the vehicle + mephedrone treatment groups. When combined with caffeine, there was a main effect observed in the dorsal striatum and the hypothalamus, however no significance was seen between groups using Tukey’s post-hoc tests in either of these regions. In contrast, the post-hoc tests showed a significant increase between the vehicle + vehicle treatment group and the vehicle + mephedrone & caffeine treatment groups observed in the nucleus accumbens shell, core, ventral striatum and pre-limbic cortex. There was no effect of WAY-100635 in any experimental condition. The results suggest that caffeine displays an additive effect when combined with mephedrone, suggesting it may exacerbate mephedrone induced serotonergic syndrome. Unlike mephedrone alone, the combination of caffeine and mephedrone does not appear to be affected by 5-HT1A receptor antagonism and more work should be completed to investigate the downstream involvement of 5-HT1B, 5-HT2A and dopaminergic receptors.
Article
Liquid chromatography (LC) and supercritical fluid chromatography (SFC) are powerful separation techniques for forensic science in the analysis of drugs, toxicology samples, trace evidence, and explosives. Combining LC and SFC with diode array detectors (DAD) can provide detection at a single wavelength or generate complete UV spectra. This advantageous pairing within forensic science allows distinguishing between classes and subclasses of compounds, discriminating positional isomers with benzene substitutions, and using library database comparison to enhance certainty of compound identification through statistical comparison. Additionally, employing DAD at single wavelengths and generation of UV spectra allow quantitation with excellent linearity, good linear range, and satisfactory limits of detection. Important for quantitation, the generation of UV spectra allows confirmation of compound identity and peak purity. The purpose of this article is to provide an overview of the qualitative and quantitative uses of LC, and SFC paired with scanning DAD within forensic science over the last ten years (2010-2020), including the analysis of seized drugs, toxicology samples, explosives, inks, and dyes. Potential benefits, limitations, and future directions for liquid phase separation paired with ultraviolet detection are considered.
Article
New toxins are constantly emerging within society. We review common toxins that cause seizure, their mechanisms, associated toxidromes, and treatments. Stimulants, cholinergic agents, gamma-aminobutyric acid (GABA) antagonists, glutamate agonists, histamine and adenosine antagonists, and withdrawal states are highlighted. Understanding current mechanisms for common toxin-induced seizures can promote understanding of future toxins and predicting if seizure may occur as a result of toxicity.
Article
Urine and oral fluid are important biological matrices used for forensic and toxicological analyses. These two complementary matrices can be used to provide information about recent and long-term drug consumption. Several analytical methods have been developed in recent years to determine different drugs of abuse in these biological samples. Most of them are based on chromatographic and related techniques, such as liquid chromatography or gas chromatography and capillary electrophoresis. Moreover, as these biological matrices can contain various compounds that may interfere with the analytes of interest, a sample pre-treatment is usually necessary. Different pre-treatment strategies have been carried out, including solid-phase extraction and liquid-liquid extraction, among others. The present review aims to provide a comprehensive overview and a discussion of the latest trends and the most used strategies for determining drugs of abuse in urine and oral fluid samples using chromatographic and electrophoretic techniques between 2018 and June 2021.
Article
In this study, a novel material of core–shell structured magnetic molecularly imprinted polymers (Fe 3 O 4 @SiO 2 @Au (FSA)-MIPs) was successfully prepared for the rapid and selective determination of 4-methylmethcathinone (mephedrone, 4-MMC). The adsorption capacity of FSA-MIPs is 34.7 mg·g ⁻¹ at 308 K, which is significantly higher than magnetic non-imprinted polymers profiting from the imprinting effect. The FSA-MIPs have a short equilibrium (20 min) and could be reused more than six times. Moreover, the selectivity coefficients of FSA-MIPs for 4-MMC, 3,4-dimethylmethcathinone, butylone, 4-ethylmethcathinone, acetylfentanyl, and methylene blue are 4.01, 5.65, 7.62, 12.30, and 20.87 respectively, further indicating the markedly enhanced binding selectivity of FSA-MIPs. As an adsorbent, the FSA-MIPs were successfully applied for effective extraction of 4-MMC in three human urine samples with the recovery rates ranging from 85.5–92.6%. The results confirmed that the FSA-MIPs have good prospects in the extraction and separation of synthetic cathinones, which is suitable for further application in the criminal sciences field.
Article
Synthetic cathinones are derivatives of cathinone, the psychoactive ingredient of the khat plant. These β-keto analogs of the corresponding α-methylphenethylamine (amphetamine) are one of the most popular categories of new psychoactive substances (NPSs), which have been widely associated with severe health problems and death by intoxication. One of the most common positions for substitution of the cathinone skeleton is the amine moiety. N-benzylated analogs of cathinones, e.g., 4-methylbenzyl cathinone (benzedrone), and related analogs display limited mass spectral information using liquid chromatography–electrospray ionization tandem mass spectrometry (LC–ESI–MS/MS). In most cases, the spectra of these analogs exhibit only product ions representing the benzyl-containing part, while the important common β-keto phenethylamine skeleton remains unidentified. We present a simple and rapid approach for the unambiguous identification of N-benzylated analogs of various synthetic cathinones based on their chemical derivatization with 2,2,2-trichloro-1,1-dimethylethyl chloroformate (TCDMECF) prior to LC–ESI–MS/MS analysis. The LC–ESI–MS/MS spectra of these cathinone analogs obtained after derivatization provided extensive fragmentation with complete coverage of all parts of the molecule, allowing the elucidation of their detailed structures and identification at a higher degree of certainty. The developed approach was further applied to distinguish and determine the structures of positional isomers of N-benzylated analogs of cathinone, which display identical ESI-MS/MS behaviors.
Article
2011年頃より本邦では多くの危険ドラッグ中毒患者が発生し,救急医療機関へ搬送された。今回,合成カチノンであるα–pyrrolidinohexiophenone(α–PHP)の経直腸投与により,多臓器不全を呈した1例を経験した。症例は35歳の男性。来院1週間前より,自慰行為の際にリキッドタイプの危険ドラッグを頻回に経直腸的に使用するようになった。来院当日に自宅マンション内でドアや浴室のガラスを破壊するなどの興奮・錯乱状態となったため救急搬送となった。来院時,瞳孔散大,高体温,高血圧,頻拍,興奮,発汗などの交感神経作動性の症状を認め,血液検査では急性腎障害,肝障害,播種性血管内凝固症候群,横紋筋融解症を認めた。挿管・人工呼吸管理,血液透析を要したが,第21病日には透析から離脱し,第30病日に後遺症なく独歩退院となった。入院時に採取した血液からは合成カチノンであるα–PHPが検出され,α–PHP中毒との確定診断に至った。本邦では危険ドラッグの規制強化後2014年末頃より,医療機関への危険ドラッグ中毒患者搬送数は激減しているが,覚醒剤と同様にアンダーグラウンド化していると考えられ,交感神経作動性トキシドロームの患者を診療した際は,合成カチノン系の危険ドラッグ中毒を鑑別に挙げる必要がある。 Numerous patients transported to emergency units of medical institutions in Japan between 2011 and 2014 have been intoxicated by novel psychoactive substances. Here, we report a case of a patient who was treated for multiple organ failure resulting from the rectal administration of synthetic cathinone, α–pyrrolidinohexiophenone (α–PHP). In 2014, a 35–year–old man was transferred to our hospital after ingesting a liquid drug, α–PHP, as detected in the patient’s serum on hospitalization. He presented with sympathomimetic toxidrome including pupil dilatation, hyperthermia, hypertension, tachycardia, confusion, and sweating. He developed acute kidney injury, liver injury, disseminated intravascular coagulation, and rhabdomyolysis and was placed on both ventilator support and hemodialysis. The patient was extubated on day 10 following admission and hemodialysis was discontinued on day 21. He was discharged in his own care on day 30. α–PHP has properties similar to those of methylenedioxypyrovalerone and mephedrone, which are both α–pyrrolidinohexiophenone derivatives. Emergency physicians should be aware of the possibly fatal toxicity of α–PHP.
Article
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The emergence of new psychoactive substances has earned a great deal of attention, and several reports of acute poisoning and deaths have been issued involving, for instance, synthetic opiates. In recent years, there have been profound alterations in the legislation concerning consumption, marketing, and synthesis of these compounds; rapid alert systems have also been subject to changes, and new substances and new markets, mainly through the internet, have appeared. Their effects and how they originate in consumers are still mostly unknown, primarily in what concerns chronic toxicity. This review intends to provide a detailed description of these substances from the point of view of consumption, toxicokinetics, and health consequences, including case reports on intoxications in order to help researchers and public health agents working daily in this area.
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This chapter highlights the similarities in chemical structure, and physiologic effects of amphetamines, as well as their therapeutic uses and potential for misuse or abuse. Special attention is given to the testing process, with an emphasis on interpretation of test results. The amphetamine‐type stimulants are a group of structurally related compounds that activate the central and peripheral nervous systems. Like cocaine, amphetamines exert their stimulant effects by increasing synaptic transmission between nerve cells. Amphetamine and related stimulants are most commonly prescribed to treat attention deficit hyperactivity disorder. Methamphetamine, the N‐methyl derivative of amphetamine, is a common drug of abuse. Paramethoxyamphetamine and paramethoxymethamphetamine are derivatives of amphetamine and methamphetamine, respectively, in which a methoxy group is attached to the para position of the phenyl ring. Immunoassays are the usual front‐line tests for amphetamines. Cathinone is a natural product found in the khat plant, which grows in eastern Africa and southern Arabia.
Chapter
More than 130 synthetic cathinones have emerged as novel psychoactive substances (NPS) over the past 15 years. Both the US Drug Enforcement Agency and Council of the European Union have implemented control measures to prohibit the use of synthetic cathinones in recent years and there has subsequently been a decline in their use. This chapter provides a general overview of the clinical implications of cathinone use, followed by focused sections reviewing data relating to pharmacology, prevalence of use, acute and chronic toxicity, and potential dependence for the more widely used cathinones.
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Synthetic cathinones are a class of novel psychoactive substances, commonly tested in seized materials by forensic chemistry laboratories. These drugs have been found in different types of seized materials including powders, tablets, liquids, herbs, and blotters. A comprehensive review of the literature shows that the analyses of synthetic cathinones have been performed by a diverse repertoire of techniques, from more traditional to emerging methods. Techniques commonly used in the analysis of “traditional” illicit drugs, such as color and microcrystalline tests, chromatography, capillary electrophoresis, mass spectrometry (MS), and infrared (IR), and Raman spectroscopies, have been used for screening and/or confirmatory purposes, depending on the technique and laboratories preference. However, other emerging techniques, such as nuclear magnetic resonance, high‐resolution MS, direct analysis in real‐time MS, gas chromatography with IR detection, and so on, have been drawing the attention of forensic scientists due to the advantages of these techniques in providing important structural data. It is important to consider that each technique presents analytical benefits and limitations, which should be considered when analyzing synthetic cathinones in seized materials. Furthermore, the combination of more than one analytical technique is always recommended, especially when an unknown synthetic cathinone is suspected and/or encountered in the sample. This article is categorized under: Forensic Chemistry and Trace Evidence > Controlled and Emerging Drug Compounds Toxicology > New Psychoactive Substances Forensic Chemistry and Trace Evidence > Emerging Technologies and Methods Analysis of synthetic cathinones in seized materials.
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Background: On the current psychopharmacological panorama, the variety of substances able to provoke an episode of acute psychosis is rapidly increasing. Such psychotic episodes are classified according to the major category of symptoms: positive, negative, or cognitive psychotic episodes. On one hand, the abuse of methamphetamines, cannabis, and cocaine plays a big role in increasing the incidence of episodes resembling a psychotic disorder. On the other hand, the progress in terms of pharmacodynamics knowledge has led to the synthesis of new drugs, such as cannabinoids and cathinone's, which have rapidly entered into the common pool of abusers' habits. Regarding these newly synthesized substances of abuse, further clinical studies are needed to understand their psychogenic properties. The topic of this review is complicated due to the frequent abuse of psychotomimetic drugs by patients affected by psychotic disorders, a fact that makes it extremely difficult to distinguish between an induced psychosis and a re-exacerbation of a previously diagnosed disorder. Methods: The present narrative review summarizes results from clinical studies, thus investigating the psychotogenic properties of abused substances and the psychotic symptoms they can give rise to. It also discusses the association between substance abuse and psychosis, especially with regards to the differential diagnosis between a primary vs. a substance-induced psychotic disorder. Findings: Our findings support the theory that psychosis due to substance abuse is commonly observed in clinical practice. The propensity to develop psychosis seems to be a function of the severity of use and addiction. Of note, from a phenomenological point of view, it is possible to identify some elements that may help clinicians involved in differential diagnoses between primary and substance-induced psychoses. There remains a striking paucity of information on the outcomes, treatments, and best practices of substance-induced psychotic episodes.
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The differentiation of a controlled drug from uncontrolled novel compounds related to regioisomers is a significant issue in forensics. The compound 1-(2,3-dihydro-1H-inden-5-yl)-2-(pyrrolidin-1-yl)butan-1-one (5-PPDI) is a novel synthetic cathinone first identified in 2015 as a new psychoactive substance. 5-PPDI is the indanyl analog of α-PBP, a typical synthetic cathinone, as well as the aliphatic ring analog of MDPBP, a synthetic cathinone with a heterocyclic ring. 5-PPDI can have three possible regioisomers, 1-(2,3-dihydro-1H-inden-1-yl)-2-(pyrrolidin-1-yl)butan-1-one (1-PPDI), 1-(2,3-dihydro-1H-inden-2-yl)-2-(pyrrolidin-1-yl)butan-1-one (2-PPDI), and 1-(2,3-dihydro-1H-inden-4-yl)-2-(pyrrolidin-1-yl)butan-1-one (4-PPDI), differing by the substituted position of the alkyl side-chain. In this study, 5-PPDI and its three regioisomers were synthesized from commercially available precursor compounds and analyzed by gas chromatography/electron ionization−quadrupole mass spectrometry (GC/EI−Q-MS) and by liquid chromatography/electrospray ionization−linear ion trap mass spectrometry (LC/ESI−LIT−MS). The four PPDI isomers could be differentiated by GC/EI−Q-MS with three types of separation columns and by 2nd generation product ion spectra (MS³) analysis using ESI−LIT−MS.
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We have investigated the metabolic profile of N-ethyl heptedrone, a new designer synthetic stimulant drug, by using data independent acquisition mass spectrometry. Phase I and phase II metabolism was studied by in vitro models, followed by liquid-chromatography coupled to mass spectrometry, to characterize and pre-select the most diagnostic markers of intake. N-ethyl heptedrone was incubated in the presence of pooled human liver microsomes. The contribution of individual enzymatic isoforms in the formation of the phase I and phase II metabolites was further investigated by using human recombinant cDNA-expressed cytochrome P450 enzymes and uridine 5’-diphospho glucuronosyltransferases. The analytical workflow consisted of liquid-liquid extraction with tert-butyl-methyl-ether at alkaline pH, performed before (to investigate the phase I metabolic profile) and after (to investigate the glucuronidation profile) enzymatic hydrolysis. The separation, identification, and determination of the compounds formed in the in vitro experiments were carried out by using liquid chromatography coupled to either high- or low-resolution mass spectrometry. Data independent acquisition method, namely sequential window acquisition of all theoretical fragment-ion spectra (SWATH®) and product ion scan were selected for high-resolution mass spectrometry, whereas multiple reaction monitoring was used for low-resolution mass spectrometry. Thirteen phase-I metabolites were isolated, formed from reactions being catalyzed mainly by CYP1A2, CYP2C9, CYP2C19 and CYP2D6 and, to a lesser degree, by CYP3A4 and CYP3A5. The phase I biotransformation pathways included hydroxylation in different positions, reduction of the ketone group, carbonylation, N-dealkylation, and combinations of the above. Most of the hydroxylated metabolites underwent conjugation reactions to form the corresponding glucurono-conjugated metabolites. Based on our in vitro observation, the metabolic products resulting from reduction of the keto group, N-dealkylation and hydroxylation of the aliphatic chain appear to be the most diagnostic target analytes to be selected as markers of exposure to N-ethyl heptedrone.
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Synthetic cathinones (SCs) are currently the second largest and the second most frequently seized group of new psychoactive substances. They are sold as replacements for controlled stimulants such as amphetamine, cocaine and MDMA. Administration of low doses of SCs can cause euphoria and increased alertness, and administration of high doses or chronic use of cathinones can cause serious adverse effects, such as hallucinations, delirium, hyperthermia, and tachycardia. In the years 2013-2019 in our practice, as many as 16 different SCs were detected in biological materials. Presented article lists the observed concentrations in 39 fatal and 18 non-fatal cases, in which a single SC as well as an SC in combination with amphetamine or ethyl alcohol were detected and quantified in biological materials. The quantitative analyses were carried out by LC-MS/MS. The analysed cases of taking SCs were associated with intoxication (2 cases), fatal intoxication (36), driving under the influence of drugs (10), and other circumstances (9), such as violence, insulting an officer, and holding a hostage. Taking SCs has serious side effects that can lead to multiple organ failure and death. Screening for the presence of SCs in biological materials should be part of the routine course of treatment in intoxication cases, both at the stage of clinical diagnosis and at the stage of forensic toxicological analysis. Ethyl alcohol and amphetamine may contribute to increased SC toxicity. This data could be valuable for further interpretation of other results from toxicological analyses.
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Significant changes in British recreational drug use were seen throughout 2009, with the emergence and rapid growth in the availability and use of substituted cathinones or ‘M-Cats’ (most notably mephedrone and methylone), a group of psychoactive drugs not currently controlled under the Misuse of Drugs Act 1971 (HM Government, 1971), with similar effects to ecstasy, cocaine and amphetamines. The reasons for the appearance and appeal of this group of so-called ‘legal highs’ are explored here in relation to availability, purity, legality and convenience. The authors argue that a reduction in the availability (and thus purity) of illegal drugs such as ecstasy and cocaine and resultant disillusionment among users was a key motivation for displacement to substituted cathinones, conveniently and legally purchased online. Finally, we explore policy considerations around the likely criminalisation of substituted cathinones and the challenge of providing rapid yet considered harm reduction responses to emergent drug trends in the face of a minimal scientific evidence base and eager press demonisation.
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Significant changes in British recreational drug use were seen throughout 2009, with the emergence and rapid growth in the availability and use of substituted cathinones or ‘M-Cats’ (most notably mephedrone and methylone), a group of psychoactive drugs not currently controlled under the Misuse of Drugs Act 1971 (HM Government, 1971), with similar effects to ecstasy, cocaine and amphetamines. The reasons for the appearance and appeal of this group of so-called ‘legal highs’ are explored here in relation to availability, purity, legality and convenience. The authors argue that a reduction in the availability (and thus purity) of illegal drugs such as ecstasy and cocaine and resultant disillusionment among users was a key motivation for displacement to substituted cathinones, conveniently and legally purchased online. Finally, we explore policy considerations around the likely criminalisation of substituted cathinones and the challenge of providing rapid yet considered harm reduction responses to emergent drug trends in the face of a minimal scientific evidence base and eager press demonisation.
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'Legal highs' are recreational drugs sold over the internet and the so-called 'head shops' all over the UK. They are freely available to buy and use as they are not covered by the Misuse of Drugs Act 1971. Mephedrone (4-methylmethcathinone) was sold as a 'legal high' until 17 April 2010 when it was made a class B drug under the Misuse of Drugs Act 1971. Numerous deaths and self-harm has been associated with mephedrone use. Effects of mephedrone are reported to be empathogenic similar to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and stimulant properties similar to cocaine. Not much is known of the effects of mephedrone on mental health. We present a case of dependence and psychosis in a patient using mephedrone (4-methylmethcathinone). The patient needed inpatient hospital care, was treated with antipsychotic olanzapine and recovered well.
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Significant changes in British recreational drug use were seen throughout 2009, with the emergence and rapid growth in the availability and use of substituted cathinones or ‘M-Cats’ (most notably mephedrone and methylone), a group of psychoactive drugs not currently controlled under the Misuse of Drugs Act 1971 (HM Government, 1971), with similar effects to ecstasy, cocaine and amphetamines. The reasons for the appearance and appeal of this group of so-called ‘legal highs’ are explored here in relation to availability, purity, legality and convenience. The authors argue that a reduction in the availability (and thus purity) of illegal drugs such as ecstasy and cocaine and resultant disillusionment among users was a key motivation for displacement to substituted cathinones, conveniently and legally purchased online. Finally, we explore policy considerations around the likely criminalisation of substituted cathinones and the challenge of providing rapid yet considered harm reduction responses to emergent drug trends in the face of a minimal scientific evidence base and eager press demonisation.
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We labelled the neuronal dopamine uptake system by using the potent dopamine uptake inhibitor GBR 12783 in its tritiated form (18.3 Ci/mmol). The binding of [3H]GBR 12783 to rat striatal membranes was saturable and specific with a Kd of 1.6 nM and a Bmax of 10.3 pmol · mg protein−1 as determined by Scatchard analysis. [3H]GBR 12783 binding to rat striatal membranes was inhibited by dopamine uptake inhibitors with IC50 highly correlated with their IC50 for inhibiting [3H]dopamine uptake by a rat striatal synaptosomal preparation. The rank order of potency was the following: GBR 12783 > amfonelic acid > mazindol > pyrovalerone > nomifensine > benztropine > amineptine > methylphenidate > cocaine. Substrates of dopamine uptake competed with [3H]GBR 12783 binding at concentrations higher than those at which they inhibited [3H]dopamine uptake. In rats with a unilateral section of the medial forebrain bundle, the decrease in [3H]GBR 12783 binding to membranes prepared from the ipsilateral striatum was equal to the decrease in [3H]dopamine uptake by a synaptosomal preparation obtained from the same striatum. [3H]GBR 12783 bound in a sodium-dependent manner to membranes prepared from striatum, nucleus accumbens and tuberculum olfactorium. GBR 12783 displayed an approximately 150-fold lower affinity for the cortical norepinephrine uptake system labelled with [3H]desipramine than for the dopamine transport complex labelled with [3H]GBR 12783. [3H]GBR 12783 appears an attractive tool for the selective characterization of the dopamine uptake system in vitro.
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Methylone (2-methylamino-1-[3,4-methylenedioxyphenyl]propane-1-one) is a synthetic hallucinogenic amphetamine analog, like MDMA (3,4-methylenedioxy- methamphetamine), considered to act on monoaminergic systems. However, the psychopharmacological profile of its cytotoxicity as a consequence of monoaminergic deficits remains unclear. We examined here the effects of methylone on the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), using a heterologous expression system in CHO cells, in association with its cytotoxicity. Methylone inhibited the activities of DAT, NET, and SERT, but not GABA transporter-1 (GAT1), in a concentration-dependent fashion with a rank order of NET > DAT > SERT. Methylone was less effective at inhibiting DAT and NET, but more effective against SERT, than was methamphetamine. Methylone alone was not toxic to cells except at high concentrations, but in combination with methamphetamine had a synergistic effect in CHO cells expressing the monoamine transporters but not in control CHO cells or cells expressing GAT1. The ability of methylone to inhibit monoamine transporter function, probably by acting as a transportable substrate, underlies the synergistic effect of methylone and methamphetamine.
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Four deaths related to the drug 4-methylmethcathinone (mephedrone) are reported. Qualitative and quantitative analysis of mephedrone was performed by high-performance liquid chromatography-diode-array detection. Of the four deaths, one was attributed to the adverse effects of mephedrone, with cardiac fibrosis and atherosclerotic coronary artery disease as a contributing factor. A 49-year-old female insufflated mephedrone; analysis disclosed mephedrone in femoral venous blood (0.98 mg/L). The second death was attributed solely to mephedrone. A 19-year-old male took mephedrone as well as alcohol and "ecstasy"; analysis disclosed mephedrone (2.24 mg/L femoral venous blood) and 3-trifluoromethylphenylpiperazine (3-TFMPP). In the third fatality, a 55-year-old female was found dead in bed; the death was attributed to the combined effects of mephedrone and methadone. Analysis of femoral venous blood revealed the prescribed drugs diazepam, nordiazepam, olazepine, and chlorpromazine metabolites together with methadone (0.3 mg/L) and mephedrone (0.13 mg/L). In the fourth case, a 17-year-old male car driver was involved in a vehicular collision and died of multiple blunt force injuries. Analysis revealed mephedrone in femoral venous blood (0.24 mg/L).
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To review and improve the evidence base regarding the toxic effects of Mephedrone, a cathinone derivative which was first believed to have been synthesised and propagated in 2007. On the 7th April 2010 the Misuse of Drugs Act 1971 (Amendment) Order 2010 was passed, declaring 4-Methylmethcathinone and other substituted cathinones Class B drugs as of 16 April 2010. This took place despite a perceived lack of evidence as to its potential harms. We undertook a critical review of the available literature to see what evidence existed for the potential effects of mephedrone ingestion. We then conducted our own retrospective consecutive case series of all patients presenting to the Aberdeen Royal Infirmary Emergency Department from the 1st December until the 16th April (the date at which Mephedrone was officially proscripted). The notes were examined for amounts, timings, sources and reasons for ingestion. Symptoms, biometric, ECG and blood analysis data were also recorded along with management and disposal outcomes. 11 articles relating to mephedrone toxicity were identified and reviewed. 89 subjects were found for our case series. This compared to only 27 patients presenting with ingestion of substances (heroin, cocaine, cannabis) at that time illegal. 30 patients stated ingestion of mephedrone in isolation and a further 27 patients stated ingestion of mephedrone with alcohol in addition. A profile of largely psychoactive and cardiovascular toxicity is described with drug naivety perhaps explaining the high rates of bingeing and addiction reported.
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Previous reports of acute toxicity/harm associated with mephedrone use have been based on self-reported mephedrone use; toxicological screening has not been undertaken in these cases to determine whether mephedrone has been used. To report the first case series of analytically confirmed mephedrone-related acute toxicity. Serum samples were collected from individuals presenting to an emergency department (ED) with acute toxicity related to self-reported mephedrone use. Toxicological analysis, by gas-chromatography coupled with mass-spectrometry and liquid chromatography with tandem mass-spectrometry was performed to qualitatively confirm mephedrone use. Symptoms/signs of acute mephedrone toxicity and basic physiological parameters were extracted from the routine ED records. Acute mephedrone-related toxicity was analytically confirmed in seven male patients; the mean ± SD age was 24.6 ± 6.5 years (range 16-36 years). Agitation (four patients) was the most common symptom/sign reported; other common symptoms/signs included: palpitations (two patients); chest pain (two patients); self-limiting pre-hospital seizures (one patient) and headaches (one patient). The mean heart rate was 109.1 ± 21.8 (range 80-140) beats per minute; one patient had a "severe" tachycardia (heart rate of ≥ 140 bpm). The mean systolic blood pressure was 153.0 ± 39.6 (range 110-210) mmHg; three patients had clinically significant hypertension (systolic blood pressure ≥ 160 mmHg). These analytically confirmed acute mephedrone toxicity presentations had clinical features of toxicity consistent with an acute sympathomimetic toxidrome (e.g. hypertension, tachycardia and agitation). These findings are similar to the pattern of toxicity seen with other sympathomimetic recreational drugs such as 3,4-Methylenedioxymethamphetamine (MDMA) and cocaine. The process for determining whether a novel psychoactive substance should be controlled often relies on demonstrated/proven acute harm associated with its use. It is important that clinical toxicologists undertake appropriate biological sampling and toxicological analyses in suspected cases of "novel psychoactive drug" toxicity. This will ensure that both clinicians and legislative authorities are informed of the confirmed pattern of toxicity associated with these drugs.
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Since the recent ban on mephedrone,1 2several alternative products have been introduced on internet websites. One of the most prominently discussed second generation products is Energy 1 (NRG-1), also advertised as naphyrone (naphthylpyrovalerone, O-2482), which originated from a group of compounds previously described in the medicinal chemistry literature.3These products are offered as legal substitutes for the recently criminalised “legal highs,” the mephedrone derivatives. One of the earlier studies exploring the motivation for using these drugs suggested that consumers think that they are more likely to be of higher purity than street drugs, carry a lower risk of physical harm, and not be liable for the criminal sanctions associated with drugs controlled under the Misuse of Drugs Act.4To obtain an initial snapshot of the post-ban situation, we purchased 17 products online from 12 UK based websites over the six weeks after the ban on mephedrone in mid-April 2010. Chemical analysis was carried out by established procedures (table 1⇓).5 View this table:View PopupView InlineNRG-1 and NRG-2 products purchased online from UK based websites in the 6 weeks after the ban on mephedroneMost of the NRG-type products were recently banned cathinones that just carried a new label; this suggests that both consumers and online sellers are, most likely without knowledge, at risk of criminalisation and potential harm. This has important health and criminal justice consequences that will require carefully thought out responses and further investigation.NotesCite this as: BMJ 2010;341:c3564FootnotesCompeting interests: None declared.References↵Morris K. UK places generic ban on mephedrone drug family. Lancet2010;375:1333-4.OpenUrlCrossRefMedlineWeb of Science↵Winstock AR, Marsden J, Mitcheson L. What should be done about mephedrone? BMJ 2010;340:c1605. (23 March.)OpenUrlFREE Full Text↵Meltzer PC, Butler D, Deschamps JR, Madras BK. 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (pyrovalerone) analogues: a promising class of monoamine uptake inhibitors. J Med Chem2006;49:1420-32.OpenUrlCrossRefMedlineWeb of Science↵Measham F, Moore K, Newcombe R, Welch Z. Tweaking, bombing, dabbing and stockpiling: the emergence of mephedrone and the perversity of prohibition. Drugs Alcohol Today2010;10:14-21.OpenUrl↵Martins CPB, Freeman S, Alder JF, Passie T, Brandt SD. Profiling psychoactive tryptamine-drug synthesis by focusing on detection using mass spectrometry. Trends Anal Chem2010;29:285-96.OpenUrlCrossRef
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