No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Khat and synthetic cathinones: A review
Abstract
For centuries, 'khat sessions' have played a key role in the social and cultural traditions among several communities around Saudi Arabia and most East African countries. The identification of cathinone as the main psychoactive compound of khat leaves, exhibiting amphetamine-like pharmacological properties, resulted in the synthesis of several derivatives structurally similar to this so-called natural amphetamine. Synthetic cathinones were primarily developed for therapeutic purposes, but promptly started being misused and extensively abused for their euphoric effects. In the mid-2000's, synthetic cathinones emerged in the recreational drug markets as legal alternatives ('legal highs') to amphetamine, 'ecstasy', or cocaine. Currently, they are sold as 'bath salts' or 'plant food', under ambiguous labels lacking information about their true contents. Cathinone derivatives are conveniently available online or at 'smartshops' and are much more affordable than the traditional illicit drugs. Despite the scarcity of scientific data on these 'legal highs', synthetic cathinones use became an increasingly popular practice worldwide. Additionally, criminalization of these derivatives is often useless since for each specific substance that gets legally controlled, one or more structurally modified analogs are introduced into the legal market. Chemically, these substances are structurally related to amphetamine. For this reason, cathinone derivatives share with this drug both central nervous system stimulating and sympathomimetic features. Reports of intoxication and deaths related to the use of 'bath salts' have been frequently described over the last years, and several attempts to apply a legislative control on synthetic cathinones have been made. However, further research on their pharmacological and toxicological properties is fully required in order to access the actual potential harm of synthetic cathinones to general public health. The present work provides a review on khat and synthetic cathinones, concerning their historical background, prevalence, patterns of use, legal status, chemistry, pharmacokinetics, pharmacodynamics, and their physiological and toxicological effects on animals and humans.
... As a result, only freshly picked khat leaves are fully efficacious (6,7). Fresh khat contains 36-343 mg of cathinone on average (8,9), as well as 83-120 mg of cathine and 8-47 mg of norephedrine per 100 g of leaves (8). Pharmacologically just like amphetamine and noradrenaline, with the ability to affect both the central and peripheral nervous systems (10). ...
... The findings in 1964 led to the United Nation Commission of Narcotic Drugs ruling against the need for universal legislation, leaving it to individual nations to choose whether health advice have to be given to users (14). Cathinone has been classified as a Schedule I substance under the Controlled Substances Act since 1993, whereas cathine was classified as a Schedule IV substance in 1988 (9). Because khat is not on the list of controlled substances, the legal status of the plant itself is frequently challenging and varies across countries (15). ...
... In Yemen, khat is legal; however in neighboring Saudi Arabia, khat is banned (16). However, it remains legal in the majority of East African countries (9). In Ethiopia, there is no clear legal restriction on khat use in Ethiopia (17). ...
Introduction
There is a paucity of data on factors associated with khat chewing among women of reproductive age using multilevel analysis. Furthermore, the effects of some potential factors like stressful life events, knowledge about and attitude toward the effects of khat have been given little attention and are not well understood. Therefore, this study aimed to examine the prevalence and multilevel factors associated with khat use among women of reproductive age in Halaba zone, South Ethiopia.
Methods
A community-based cross sectional study was conducted in Halaba zone from February to July, 2023. Systematic random sampling technique was used to include 1573 study participants. The dependent variable was current khat use, which is operationalized as using khat within 30 days preceding the study. An interviewer administered questionnaire was used for the data collection.
Results
The prevalence of current khat use among women of reproductive age was 65.9% [95%CI (63.5-68.2%)]. Factors significantly associated with khat use were; ages of women 35 and above years [Adjusted Odds Ratio (AOR) = 6.35, 95% CI: (3.62, 11.13)], ever married [AOR = 2.41, 95% CI: (1.10, 5.31)], secondary and above education [AOR = 0.28, 95% CI: (0.15, 0.49)], belong to richer household [AOR = 1.75, 95% CI: (1.12, 2.75)], mass media use [AOR = 3.12, 95% CI: (1.85, 4.81)], low knowledge about khat effects [AOR = 3.12, 95% CI: (1.85, 5.24)], positive attitude towards khat use [AOR = 11.55, 95% CI: (6.76, 19.71)], and strong social support [AOR = 0.43, 95% CI: (0.28, 0.64)] and non-user friend [AOR = 0.31, 95% CI: (0.20, 0.48)]. From the community level variables: rural residence [AOR = 5.06, 95% CI: (1.82, 14.09)] was significantly associated with khat use.
Conclusion
Khat use among women of reproductive age was found to be very high. From individual-level factors: advanced ages of women, secondary and above education, live in the richer wealth quintile, mass media exposure, low knowledge on khat effects, positive attitude towards khat use, strong social support, and from community-level variables: residing in rural area were significantly associated with khat use. Khat use screening for all women of childbearing age, as well as referral to substance use disorder centers for those women identified as having khat use disorder, should become a standard of care in all health facilities.
... Synthetic cathinones are the largest sub-class of the synthetic stimulants category of NPS, and they are abused for their amphetamine-like effects [9,10]. The core phenylalkylamine structure of synthetic cathinones is designed to mimic cathinone, which is a natural chemical found in the Catha edulis plant that is known to provide stimulant-like properties [6,9]. ...
... Synthetic cathinones are the largest sub-class of the synthetic stimulants category of NPS, and they are abused for their amphetamine-like effects [9,10]. The core phenylalkylamine structure of synthetic cathinones is designed to mimic cathinone, which is a natural chemical found in the Catha edulis plant that is known to provide stimulant-like properties [6,9]. Synthetic cathinones were first marketed through headshops and the internet in attractive packaging signaling use for consumption, but with labeling such as "bath salts," "plant food," or "not for human consumption" as a mechanism to avoid legislative restrictions [6]. ...
... In June 2021, N-ethyl pentylone, also known as ephylone, was permanently scheduled as a Schedule I controlled substance according to the U.S. Controlled Substances Act [12]. However, because synthetic cathinone scheduling is completed on a case-by-case basis, only minor structural modifications are required to avoid the existing legislative restrictions [9]. ...
... Łatwa dostępność substratów i stosunkowo prosta synteza katynonu przyczyniły się do poszukiwania i otrzymania nowych związków o podobnej strukturze i działaniu jak cząsteczka prototypowa, które nazwano syntetycznymi katynonami [4,5]. Ze względu na praktycznie nieograniczoną możliwość modyfikacji struktury katynonu i kolejne modyfikacje otrzymanych już pochodnych, polegające na przykład na wprowadzaniu nowych podstawników (alkilowych, alkoksylowych, fluorowcowych) do pierścienia aromatycznego, syntetyczne katynony są obecnie najczęściej identyfikowanymi NPS [5]. ...
... Nagromadzenie DA może skutkować jej autooksydacją i wytworzeniem toksycznych półproduktów (chinonów, semichinonów) oraz reaktywnych form tlenu i azotu (ang. reactive oxygen and nitrogen species, RONS) [4,22]. Podobny mechanizm dotyczy neuronów serotoninergicznych, w których na skutek wzrostu poziomu 5-HT w przestrzeni synaptycznej dochodzi do powstania neurotoksycznych dihydroksybitryptamin [23]. ...
... α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate), nadprodukcję RONS oraz aktywację proapoptotycznych szlaków sygnałowych [22,24]. Ponadto, syntetyczne katynony zaburzają równowagę redoks neuronów na skutek wyczerpania zredukowanego glutationu (GSH) i wzrostu poziomu glutationu utlenionego (GSSG) [4]. ...
Syntetyczne katynony są grupą najczęściej identyfikowanych substancji psychoaktywnych o silnym efekcie stymulującym i wysokim potencjale uzależniającym. Obecnie uważa się, że zażywanie tych związków zwiększa ryzyko wystąpienia sporadycznych postaci chorób neurozwyrodnieniowych. W artykule przedstawiono aktualne poglądy dotyczące mechanizmów neurotoksycznego działania syntetycznych katynonów obejmujące: zaburzenia bariery krew-mózg, dysfunkcje mitochondriów, stres oksydacyjny, neurozapalenie i hipertermię. Dalsze poznanie komórkowych i molekularnych procesów leżących u podstaw neurotoksyczności i związanych z nią objawów klinicznych jest konieczne w opracowaniu strategii terapeutycznych do zapobiegania i leczenia schorzeń neuropsychiatrycznych wynikających z przyjmowania syntetycznych katynonów.
... They resemble amphetamine derivatives except that there is a carbonyl group in the β-position of the aminoalkyl chain. All possible derivatives are formed by attaching substituents to the basic cathinone structure at several typical positions (Figure 2) (Valente et al., 2014). ...
... Structurally, cathinone derivatives can be classified into four groups ( Table 1) (Valente et al., 2014). Groups III and IV are often referred to jointly as 'pyrovalerone derivatives' or 'pyrovalerones'. ...
... There are also several derivatives that cannot be assigned to any of the groups. These are substances formed by replacing a phenyl group with another (thiophene or naphthyl) ring ( Figure 3) (Gambaro et al., 2016;Valente et al., 2014). It is worth noting that the carbon atom to which the amino group is attached is the stereogenic centre of the molecule, but the vast majority of SCs products exist in racemic form (Simmons et al., 2018). ...
Objective
To review the literature on the neuropharmacology of synthetic cathinones.
Methods
A comprehensive literature search was carried out across multiple databases (mainly PubMed, World Wide Web, and Google Scholar) using relevant keywords.
Results
Cathinones exhibit a broad toxicological profile, mimicking the effects of a wide variety of ‘classic drugs’ such as 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine and cocaine. Even small structural changes affect their interactions with key proteins. This article reviews existing knowledge of the mechanisms of action of cathinones at the molecular level, and key findings from research on their structure-activity relationship. The cathinones are also classified according to their chemical structure and neuropharmacological profiles.
Conclusions
Synthetic cathinones represent one of the most numerous and widespread groups among new psychoactive substances. Initially developed for therapeutic purposes, they quickly started to be used recreationally. With a rapidly increasing number of new agents entering the market, structure-activity relationship studies are valuable for assessing and predicting the addictive potential and toxicity of new and potential future substances. The neuropharmacological properties of synthetic cathinones are still not fully understood. A full elucidation of the role of some key proteins, including organic cation transporters, requires detailed studies.
... Methcathinone was one of the first ever synthetic cathinones and was meant to reach the market as an antidepressant. Other examples are pyrovalerone, explored as a treatment for obesity, chronic fatigue, and lethargy, and methylone as a potential antidepressant and anti-Parkinson's agent [3][4][5]. Nevertheless, these compounds never reached the market due to powerful addictive properties [6]. To this day, only the synthetic cathinone bupropion reached the market, being currently used as an antidepressant and a support to smoking cessation [7]. ...
... This work focused on 3,4-methylenedioxypyrovalerone (MDPV), one of the most abused synthetic cathinones worldwide [25]. MDPV comprises a heterocyclic structure with a 3,4-methylenedioxi ring and a pyrrolidine ring (Figure 2), making this derivative part of the group of 3,4-methylenedioxypyrrolidinophenones or mixed cathinones [3]. Some studies have reported differences between the behavior of enantiomers of compounds in the permeability across the Caco-2 cell line [21,22]. ...
... This work focused on 3,4-methylenedioxypyrovalerone (MDPV), one of the most abused synthetic cathinones worldwide [25]. MDPV comprises a heterocyclic structure with a 3,4-methylenedioxi ring and a pyrrolidine ring (Figure 2), making this derivative part of the group of 3,4-methylenedioxypyrrolidinophenones or mixed cathinones [3]. The main goal of this work was to investigate the intestinal permeability across the gastrointestinal tract and potential enantioselectivity of MDPV using the in vitro Caco-2 model. ...
3,4-Methylenedioxypyrovalerone (MDPV) is a widely studied synthetic cathinone heterocycle mainly concerning its psychoactive effects. It is a chiral molecule and one of the most abused new psychoactive substances worldwide. Enantioselectivity studies for MDPV are still scarce and the extent to which it crosses the intestinal membrane is still unknown. Herein, an in vitro permeability study was performed to evaluate the passage of the enantiomers of MDPV across the Caco-2 monolayer. To detect and quantify MDPV, a UHPLC-UV method was developed and validated. Acceptable values within the recommended limits were obtained for all evaluated parameters (specificity, linearity, accuracy, limit of detection (LOD), limit of quantification (LOQ) and precision). The enantiomers of MDPV were found to be highly permeable across the Caco-2 monolayer, which can indicate a high intestinal permeability. Enantioselectivity was observed for the Papp values in the basolateral (BL) to apical (AP) direction. Furthermore, efflux ratios are indicative of efflux through a facilitated diffusion mechanism. To the best of our knowledge, determination of the permeability of MDPV across the intestinal epithelial cell monolayer is presented here for the first time.
... Cathinone (Figure 1), a β-keto analog of amphetamine, is a monoamine alkaloid found in Catha edulis (khat), producing psychostimulant effects akin to substances like amphetamine [1]. Synthetic cathinones (SCs) are β-keto analogues of cathinone, with cathinone's backbone structure having four modification positions, the aromatic ring (R1), alkyl side chain (R2), and amino group (R3 and R4), allowing for the synthesis of a wide range of derivatives [2,3]. SCs can be classified into four sub-classes based on their structural modifications [3,4]: (1) N-alkyl cathinones, (2) N-pyrrolidine cathinones, (3) 3,4methylenedioxy-N-pyrrolidine cathinones, and (4) 3,4-methylenedioxy-N-alkyl cathinones. ...
... Synthetic cathinones (SCs) are β-keto analogues of cathinone, with cathinone's backbone structure having four modification positions, the aromatic ring (R1), alkyl side chain (R2), and amino group (R3 and R4), allowing for the synthesis of a wide range of derivatives [2,3]. SCs can be classified into four sub-classes based on their structural modifications [3,4]: (1) N-alkyl cathinones, (2) N-pyrrolidine cathinones, (3) 3,4methylenedioxy-N-pyrrolidine cathinones, and (4) 3,4-methylenedioxy-N-alkyl cathinones. Notably, 4-methylmethcathinone (mephedrone, Figure 1), 3,4-methylenedioxypyrovalerone (MDPV, Figure 1), and 3,4-methylenedioxy-N-methylcathinone (methylone, Figure 1) are the most commonly used SCs. ...
Synthetic cathinones, derived from cathinone found in the plant Catha edulis, represent the second largest and most frequently seized group of new psychoactive substances. They are considered as β-keto analogs of amphetamine, sharing pharmacological effects with amphetamine and cocaine. This review describes the neurotoxic properties of synthetic cathinones, encompassing their capacity to induce neuroinflammation, dysregulate neurotransmitter systems, and alter monoamine transporters and receptors. Additionally, it discusses the rewarding and abuse potential of synthetic cathinones drawing from findings obtained through various preclinical animal models, contextualized with other classical psychostimulants. The review also offers an overview of current abuse trends of synthetic cathinones on the illicit drug market, specifying the aspects covered, and underscores the risks they pose to public health. Finally, the review discusses public health initiatives and efforts to reduce the hazards of synthetic cathinones, including harm reduction methods, education, and current clinical management strategies.
... Catinonas sintéticas são análogos estruturais do alcaloide catinona (1) (Figura 2) -um produto natural com propriedade psicoativa que foi originalmente isolado da planta Catha edulis, conhecida popularmente como khat [33]. O efeito psicoestimulante das catinonas é conhecido por povos originários para alívio da fadiga, a partir da mastigação das folhas de Catha edulis [34]. ...
... O efeito estimulante se dá pela inibição da monoaminoxidase (MAO), enzima responsável pela degradação da dopamina [35]. As catinonas sintéticas possuem estrutura similar às anfetaminas, se diferenciando destas pela presença de um grupo cetona na posição beta em relação ao grupo amino presente na cadeia alquílica [33]. Existe uma grande variedade de catinonas sintéticas oriundas da modificação, seja ela estrutural e/ou eletrônica, dos substituintes do anel aromático (R 1 ) (e da posição destes substituintes), da inserção de substituintes e modificação da cadeia alquílica (R 2 e/ou R 3 ) e/ou da modificação/transformação do grupo amino (R 4 e/ou R 5 ) presentes nessa classe de substâncias sintéticas (Figura 2) [36]. ...
Centenas de substâncias psicoativas inéditas são identificadas por ano em escala global. Estas substâncias são classificadas como Novas Substâncias Psicoativas (NSP) e se originam da alteração da estrutura química de drogas ilícitas já existentes. Com o aumento significante de substâncias, faz-se necessário a pesquisa e desenvolvimento de métodos de detecção de rápida aplicação e baixo custo. Esse artigo de revisão apresenta os métodos colorimétricos clássicos e contemporâneos para detecção das drogas apreendidas em escala nacional, de 2015 a 2020, e estadual de 2008 a 2017. Os testes colorimétricos consolidados para drogas clássicas apresentam resultados promissores para detecção de novas substâncias psicoativas, além disso, novos métodos foram desenvolvidos para detecção com maior especificidade e sensibilidade dessas substâncias. Dessa forma, o desenvolvimento e adaptação de métodos colorimétricos são uma proposta apropriada para detecção e direcionamento para identificação de drogas ilícitas clássicas e contemporâneas.
... Only several hypotheses are currently proposed. Being structurally similar and having similar mechanisms of action to amphetamine and MDMA, it is assumed that 3-MMC might share some mechanisms of toxicity with these substances [1,[46][47][48]. Like amphetamine, 3-MMC shows the capability to induce hyperthermia, which was described by Bäckberg et al. [23]. ...
... Da Silva et al. [52] conducted a study aimed at assessing the hepatotoxicity of 3-MMC using primary rat hepatocytes. According to the fact that the liver has an important role in cathinones' metabolism [46], particularly after administered per os, it is of current scientific opinion that metaphedrone undergoes bioactivation that produces metabolites with higher toxicity, which are believed to be capable of inducing harm to the functioning of the liver and thus to the overall homeostasis of the intoxicated individual [52]. The results of their investigation showed that the liver is indeed sensitive to 3-MMC-induced toxicity and the extent of damage to the cells seems to be directly proportional to the concentration of the drug to which they were exposed. ...
Introduction: Synthetic cathinones are a group of novel psychoactive substances used as an alternative to classical recreational drugs. As a result of legal prohibitions on older generations of these compounds, new formulations appeared on the drug market. One of them is metaphedrone (3-methylmethcathinone, 3-MMC), a structural isomer of 4-methylmethcathinone and a psychostimulant drug. Metaphedrone became popular in a large number of countries in a short period of time. The aim: The collection, analysis, and review of relevant research on the subject of metaphedrone in order to present information about the pharmacological, clinical, and toxicological profile of this compound. An assessment of the significance and role of metaphedrone in consumption patterns of novel psychoactive substances among recreational drug users. Methodology: By using search engines like Google Scholar and PubMed, the relevant literature on metaphedrone was looked for and analyzed. The search was not limited to a specific period of time. All information regarding the compound of interest was analyzed and presented. Key results and discussion: All novel psychoactive substances are abused due to their pronounced stimulatory, hallucinogenic, dissociative, and euphoric and/or relaxing characteristics. Users of 3-methylmethcathinone usually opt for this substance for recreational purposes and/or sexual stimulation. Metaphedrone has the potential to cause a psychological dependence to the users. It was determined in relevant studies that most users are from 17 to 50 years of age. Older users usually administer metaphedrone intravenously, while younger ones usually choose snorting and oral ingestion of the drug. In Serbia, metaphedrone is a legally controlled substance. The pharmacodynamic properties make metaphedrone similar to classical recreational drugs. The method of administration, mainly repeated administration in a single session, could be explained using the pharmacokinetic profile of the drug. The most reported symptoms of intoxication were those of a sympathomimetic nature, such as tachycardia, chest pain, hypertension, diaphoresis, and agitation. Most intoxications and fatal outcomes occurred to users who combined several psychoactive substances. The correlation between measured blood concentrations of the drug and outcomes of intoxication was not found. The mechanisms of metaphedrone’s toxicity are not fully understood. Conclusions: There is an increasing trend of abuse of metaphedrone among recreational drugs users. Future studies should focus on pharmacological and toxicological effects of metaphedrone on animals and humans.
... Synthetic cathinones constitute a heterogenous class of NPS, structurally related to cathinone, which is a monoamine alkaloid found in the leaves of shrub Catha edulis (also known as khat). Khat use is highly prevalent in East African and Middle Eastern countries, in particular in Somalia and Yemen, and it is an emerging problem in Australia and Europe (25). ...
... Both cathinone and cathine are close chemical relatives of the phenethylamines/amphetamine, and the pharmacological effects of cathinone are qualitatively similar to those of amphetamine, although it is less potent. Cathinone and cathine are listed in the 1971 United Nations Convention on Psychotropic Substances under Schedules I and III respectively (25). Moreover, these substances are controlled in almost all European countries: in Italy they are included in Table I of the DPR 309/90 (26). ...
In this Chapter, we describe the main classes of substances of abuse and their mechanisms of action.
... Besides, the little information available on their pharmacology and toxicology can result in harmful consequences [2,3]. Since most NPS are typically not controlled, they are easily available online or on the street market under the names "research chemicals", "bath salts", or "plant food" [4][5][6]. In the last decades, the category of synthetic cathinones (SCs) has seen a rise in its popularity worldwide, particularly among the young population [5,6]. ...
... Since most NPS are typically not controlled, they are easily available online or on the street market under the names "research chemicals", "bath salts", or "plant food" [4][5][6]. In the last decades, the category of synthetic cathinones (SCs) has seen a rise in its popularity worldwide, particularly among the young population [5,6]. In 2020, SCs accounted for 65% of NPS material seized in Europe. ...
Synthetic cathinones, one of the most prevalent categories of new psychoactive substances, have been posing a serious threat to public health. Methylmethcathinones (MMCs), notably 3-MMC, have seen an alarming increase in their use in the last decade. The metabolism and toxicology of a large majority of synthetic cathinones, including 3-MMC and 2-MMC, remain unknown. Traditionally, male-derived liver materials have been used as in vitro metabolic incubations to investigate the metabolism of xenobiotics, including MMCs. Therefore, little is known about the metabolism in female-derived in vitro models and the potential sex-specific differences in biotransformation. In this study, the metabolism of 2-MMC, 3-MMC, and 4-MMC was investigated using female rat and human liver microsomal incubations, as well as male rat and human liver microsomal incubations. A total of 25 phase I metabolites of MMCs were detected and tentatively identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Seven sex-specific metabolites were detected exclusively using pooled male rat liver microsomal incubations. In addition, the metabolites generated from the sex-dependent in vitro metabolic incubations that were present in both male and female rat liver microsomal incubations showed differences in relative abundance. Yet, neither sex-specific metabolites nor significant differences in relative abundance were observed from pooled human liver microsomal incubations. This is the first study to report the phase I metabolic pathways of MMCs using in vitro metabolic incubations for both male and female liver microsomes, and the relative abundance of the metabolites observed from each sex.
Graphical abstract
... Synthetic cathinones constitute a heterogenous class of NPS, structurally related to cathinone, which is a monoamine alkaloid found in the leaves of shrub Catha edulis (also known as khat). Khat use is highly prevalent in East African and Middle Eastern countries, in particular in Somalia and Yemen, and it is an emerging problem in Australia and Europe (25). ...
... Both cathinone and cathine are close chemical relatives of the phenethylamines/amphetamine, and the pharmacological effects of cathinone are qualitatively similar to those of amphetamine, although it is less potent. Cathinone and cathine are listed in the 1971 United Nations Convention on Psychotropic Substances under Schedules I and III respectively (25). Moreover, these substances are controlled in almost all European countries: in Italy they are included in Table I of the DPR 309/90 (26). ...
New psychoactive substances (NPS) are psychotropic drugs, that are used as alternatives to the classical scheduled drugs of abuse and are not under control of the United Nations' 1961 Narcotic Drugs/1971 Psychotropic Substances conventions. NPS is a umbrella generic term including new synthetic and natural drugs such as synthetic cannabinoids, synthetic opioids, hallucinogens, synthetic cathinones and other stimulants. Many NPS were originally developed as therapeutic drug candidates and/or as pharmacological tools to investigate endogenous systems, although none of them were clinically tested. Due to the absence of experimental and clinical data of on NPS, pharmacological and toxicological data are rarely available. Therefore, NPS use may induce unknown and unexpected effects, including acute and chronic toxic effects, as reported in numerous cases of intoxication and deaths in Europe and worldwide. The rapid emergence of a large number of NPS on the global drug market poses a significant risk to public health and a challenge to drug policy. The present manuscript provides an updated review of the large number of new/novel/ emerging psychoactive substances and their associated psychopathological consequences.
... The purity and composition of these substances are also health threats. The use of synthetic stimulants was developed to treat patients who have Parkinson's disease, obesity, and depression [14,132,133]. More recently, they have been used as cognitive enhancers (commonly used by students or professionals who need to focus when working in stressful environments), to enhance athletes' performance and to help people lose weight [14,134,135]. ...
Drug abuse represents a significant public health problem with a growing tendency. As a way of circumventing the strict national and international control of psychoactive substances by regulatory agencies, there is a market release of new substances with psychoactive activity, called New Psychoactive Substances (NPSs). This group of substances encompasses a diverse range of synthetic compounds designed to mimic the effects of traditional illicit substances. As NPSs show stronger psychoactive effects than classical drugs, they pose unique challenges to public health and regulatory frameworks. Additionally, some substances are considered NPSs in some countries but not in others. Therefore, based on a given legal definition, manufacturers can create an NPS that does not fall under that definition and thus is not prohibited. This review critically explores the multifaceted dimensions of the criminal and legal contexts associated with NPSs. It examines the trends of abuse, the intricate network of criminal and legal aspects surrounding these substances, and the crucial warning signs that indicate their emergence, highlighting the health risks posed by these substances. In conclusion, this manuscript addresses the intricate interplay between the pharmacology, risks, and regulatory responses. These multifaceted challenges associated with NPSs will likely provide valuable insights for future research.
... The total number of studied molecules was 75, and they are shown in the Supplementary Materials (Tables S1-S5). Amphetamines [15,37,55,67,68] Cathinones [39,53,54,[69][70][71][72] Psychoactives 2024, 3, FOR PEER REVIEW 5 Figure 1. Categories for drug analysis as suggested for SWGDRUG [36]. ...
Novel psychoactive substances (NPSs) are compounds plotted to modify the chemical structures of prohibited substances, offering alternatives for consumption and evading legislation. The prompt emergence of these substances presents challenges in health concerns and forensic assessment because of the lack of analytical standards. A viable alternative for establishing these standards involves leveraging in silico methods to acquire spectroscopic data. This study assesses the efficacy of utilizing infrared spectroscopy (IRS) data derived from density functional theory (DFT) for analyzing NPSs. Various functionals were employed to generate infrared spectra for five distinct NPS categories including the following: amphetamines, benzodiazepines, synthetic cannabinoids, cathinones, and fentanyls. PRISMA software was conceived to rationalize data management. Unsupervised learning techniques, including Hierarchical Cluster Analysis (HCA), Principal Component Analysis (PCA), and t-distributed stochastic neighbor embedding (t-SNE), were utilized to refine the assessment process. Our findings reveal no significant disparities among the different functionals used to generate infrared spectra data. Additionally, the application of unsupervised learning demonstrated adequate segregation of NPSs within their respective groups. In conclusion, integrating theoretical data and dimension reduction techniques proves to be a powerful strategy for evaluating the spectroscopic characteristics of NPSs. This underscores the potential of this combined methodology as a diagnostic tool for distinguishing IR spectra across various NPS groups, facilitating the evaluation of newly unknown compounds.
... Synthetic cathinone more commonly referred to as analogs of cathinone (Baumann et al., 2018;Yadav-Samudrala et al., 2019), naturally occurring stimulant found in the Khat plant (Catha edulis) that has been used as a prototype for various synthetic cathinone derivatives. Cathinone can be substituted at an aromatic ring, amino group, or alkyl chain to develop different derivatives (Valente et al., 2014). On this basis, we have categorized them into different groups, Group A consists of the most common derivatives, N-alkyl derivatives with the alkyl group substituted at an alpha carbon atom such as Methcathinone (MCTH), Ethcathinone (ECTH), Group B includes molecules substituted at any position of an aromatic ring and alpha carbon atom, viz Mephedrone (MPD), Buphedrone (BPD), Pentedrone (PTDN) (Majchrzak et al., 2018), and 3,4-Dimethylmethcathinone (3,4-DMCTH). ...
In a step towards understanding the structure–property relationship among Synthetic Cathinones (SCs),
a combined methodology based on Density Functional Theory (DFT), Administration, Distribution,
Metabolism, Excretion, and Toxicity (ADMET) predictions, docking and molecular dynamics simulations
have been applied to correlate physicochemical descriptors of various SCs to their biological activity.
The results from DFT and molecular docking studies correlate well with each other explaining the biological
activity trends of the studied SCs. Quantum mechanical descriptors viz. polarizability, electron
affinity, ionization potential, chemical hardness, electronegativity, molecular electrostatic potential, and
ion interaction studies unravel the distinguishingly reactive nature of Group D (pyrrolidine substituted)
and Group E (methylenedioxy and pyrrolidine substituted) compounds. According to ADMET analysis,
Group D and Group E molecules have a higher probability of permeating through the blood–brain barrier.
Molecular docking results indicate that Phe76, Ala77, Asp79, Val152, Tyr156, Phe320, and Phe326
constitute the binding pocket residues of hDAT in which the most active ligands MDPV, MDPBP, and
MDPPP are bound. Finally, to validate the derived quantum chemical descriptors and docking results,
Molecular Dynamics (MD) simulations are performed with homology-modelled hDAT (human dopamine
transporter). The MD simulation results revealed that the majority of SCs remain stable within the hDAT
protein’s active sites via non-bonded interactions after 100 ns long simulations. The findings from DFT,
ADMET analysis, molecular docking, and molecular dynamics simulation studies complement each other
suggesting that pyrrolidine-substituted SCs (Group D and E), specifically, MPBP and PVN are proven
potent SCs along with MDPV, validating various experimental observations.
... These compounds almost do not have any medical use regarding the undesired effects due to abuse and dependence that they cause. Their quasi legality, lower prices, and possibility to mimic the effects of traditional drugs especially cocaine, amphetamine, methamphetamine, and 3,4-methylene dioxymethamphetamine (MDMA) make them especially suitable for abuse [5][6][7][8]. One of the synthetic cathinones which was identified for the first time in 2014 and started to appear more often in USA and some European countries in 2016 is NEP, known also as b,k-ethyl K or ephylone [4,[9][10][11]. ...
One of the new synthetic cathinones that has a high tendency to replace ecstasy and other established synthetic drugs is N-ethylpentylone, (NEP), due to its high potency, stimulative, hedonic and hallucinatory effects. In order to examine the interactions of N-ethylpentylone, the apparent molar quantities, thermal expansion coefficient and the apparent molar volume at infinite dilution were calculated from the experimental measurements of the density of NEP aqueous solutions in different temperature and molality ranges, from T = (293.15 to 313.15) K and from m = (0.0590 to 0.0977) mol·kg⁻¹, respectively. The taste of N-ethylpentylone was estimated by calculated values of apparent specific molar volume at infinite dilution and it was concluded that its taste in aqueous solutions is bitter. Also, using the spectrofluorimetric technique, an intermolecular deactivation of in situ formed ethidium bromide (EB) complex with DNA (EB-DNA) was investigated in the presence of N-ethylpentylone. Obtained results indicated good affinity and efficiency of NEP to substitute EB from the EB-DNA complex via intercalation mode. Using molecular docking, it was concluded that the binding energy obtained for NEP indicates its higher affinity to interact with DNA, compared to methamphetamine and amphetamine, but lower compared to ecstasy. The affinity of NEP to bind to bovine serum albumin (BSA) was also investigated and discussed. It is shown that N-ethylpentylone could be efficiently transported and distributed through the blood and cells.
... The extent of pharmacological actions of khat depends on the khat type [35]. Previous research has shown that fresh leaves of khat contain more than 40 chemicals [9,32] including alkaloid chemicals, sterols, tannins, amino acids, terpenoids, minerals, vitamins [46], ascorbic acid [95], flavonoids [96], carbohydrates, glycosides and non-toxic metals ...
With increasing stress levels, disease burden and harsh
economic times, drug abuse has increased significantly.
Currently, control measures aimed at curbing drug abuse have
been applied by various authorities with little success. This
paper focuses specifically on one of the emerging drug
substances that have been ignored for centuries – Catha edulis.
The consumption of khat (Catha edulis) is mainly through
chewing of young fresh shoots, sprinkling dry crushed leaves of
khat on already prepared food, smoking, and boiling dried khat
leaves in water to form Abyssinian tea. The use of khat has
spread to many communities of the world such as the United
States of America, Canada, the United Kingdom, and the
Netherlands. This has been brought about by a high number of
immigrants notably from East Africa and the Middle East,
improved road and air transport networks, and improved
preservation methods. Chronic and excessive use of khat may
result in serious medical concerns among khat users. The
medical effects of khat depends on the amount and potency of
the chemical cathinone and cathine that is taken in or being
absorbed. This work, therefore, reviews the current knowledge
on the health effects of khat, social benefits, and possible
negative impacts of khat use. Moreover, this work also clearly
outlines cessation strategies towards curbing chronic khat
abuse, withdrawal symptoms, and pharmacology. It also
identifies and recognizes the role of government authorities,
non-governmental institutions, and society in addressing the
medical problems associated with the consumption of khat.
... In 2011, Spiller et al. (2011) firstly measured the blood concentrations of the then-prevalent synthetic cathinone MDPV (3,4-Methylenedioxypyrovalerone) exposure by reviewing synthetic cathinone related cases from two US poison centers and indicated that its clinical effects manifested as a sympathomimetic syndrome, including psychotic episodes, movement disorders, and tachycardia. In terms of toxicological mechanisms, several studies showed that dysregulation of the central monoamine system was the main mechanism underlying the adverse effects and associated psychiatric behaviors of synthetic cathinone (Coppola and Mondola, 2012;Valente et al., 2014). Notably, these ten most cited articles were all published between 2010 and 2015, suggesting that these results had progressed and verified the basic pharmacological and N represents published article numbers by journals. ...
Nowadays, NPS abuse are continuing to expand in terms of harm and scope, due to its cheap and easy to manufacture anywhere in the world. This study reviewed articles related to seven heavily abused NPS to analyze the structure and trends of NPS abuse. A total of 2476 articles were retrieved based on the search strategy for bibliometric analysis. A significant trend of research in recent years was the increasing number of research on synthetic opioids and designer benzodiazepines, but synthetic cannabinoid and synthetic cathinone still dominate, which were mainly concerned with the development of metabolic models and determining methods as well as their abuse characteristics and reasons. However, with the introduction of class-wide ban on synthetic cannabinoid in China and a series of enhancements in other countries, the abuse of it might decrease to some extent, but more than 20 kinds of synthetic cannabinoid beyond the scope of ban in China still reminded researchers of their potential threats. As for synthetic cathinone, an important phenomenon was some of the drugs first identified during certain period might be more widely distributed in the future. Besides, several problems such as the regulation and prevention mode of emerging NPS, development of testing technologies as well as the interpretation and identification of multiple NPS combinations were also worth paying attention to. This study could help entrants better understand the structure of NPS abuse and provided direction for future research in forensic toxicology.
... These drugs are β-ketogenic analogs of phenethylamines, chemically and structurally related to cathinone, a monoamine alkaloid responsible for the psychoactive properties of the plant Khat (Catha edulis) [1][2][3]. The ease of synthesis and introduction of substituents on the aromatic ring, alpha carbon, and amino group of the natural cathinone molecule gave rise to a variety of synthetic analogs [4]. ...
3',4'-Methylenedioxy-N-tert-butylcathinone (MDPT), also known as tBuONE or D-Tertylone, is a synthetic cathinone (SC) frequently abused for recreational purposes due to its potent stimulant effects and similarity to illegal substances like methamphetamine and ecstasy. The structural diversity and rapid introduction of new SC analogs to the market pose significant challenges for law enforcement and analytical methods for the preliminary screening of illicit drugs. In this work, we present, for the first time, the electrochemical detection of MDPT using screen-printed electrodes modified with carbon nanofibers (SPE-CNF). MDPT exhibited three electrochemical processes (two oxidations and one reduction) at SPE-CNF. The proposed method for MDPT detection was optimized in 0.2 mol L−1 Britton-Robinson buffer solution at pH 10.0 using differential pulse voltammetry (DPV). The SPE-CNF showed high stability for electrochemical responses of all redox processes of MDPT using the same or different electrodes, with relative standard deviations less than 4.7 % and 1.5 % (N=3) for peak currents and peak potentials, respectively. Moreover, the proposed method provided a wide linear range for MDPT determination (0.90-112 µmol L−1) with low LOD (0.26 µmol L−1). Interference studies for two common adulterants, caffeine and paracetamol, and ten other illicit drugs, including amphetamine-like compounds and different SCs, showed that the proposed sensor is highly selective for the preliminary identification of MDPT in seized forensic samples. Therefore, SPE-CNF with DPV can be successfully applied as a fast and simple screening method for MDPT identification in forensic analysis, addressing the significant challenges posed by the structural diversity of SCs.
... The major active substances of khat include several alkaloids, tannins, and flavonoids, of which the phenylpropylamine derivative cathinone (S-(−)-α-aminopropiophenone) is the main psychoactive alkaloid, and the phenylpropanolamine diastereomer cathine (S,S-(+)-norpseudoephedrine) is a less-psychoactive component. Both affect the central and peripheral nervous systems [4]. ...
Khat (Catha edulis) is an evergreen shrub whose buds and leaves give a state of delight and euphoria when chewed. Cathinone, an amphetamine-like stimulant that is among the active ingredients in khat, is able to downregulate glutamate transporter subtype I (GLT-1). Neurobehavioral dysfunctions such as altered locomotor activity, anorexia, and nociception have been observed in animals exposed to cathinone. Interestingly, treatment with a β-lactam antibiotic such as ceftriaxone, which upregulates GLT-1, normalizes cathinone-induced conditioned place preference, and alters repetitive movements in rats. However, little is known about the role of the glutamatergic system in memory dysfunction and anxiety-like behaviors in mice exposed to khat. We found here that clavulanic acid, a β-lactam-containing compound and GLT-1 upregulator, would modulate the neurobehavioral changes, including memory impairment and anxiety-like behaviors, associated with repeated exposure of mice to khat. Our data supported that clavulanic acid could improve memory impairment and anxiety-like behaviors through upregulating GLT-1 in the nucleus accumbens (NAc), an effect abolished with a selective GLT-1 blocker. This upregulation was associated with restored glutamate/cystine antiporter expression in the NAc using a Western blotting assay. Cathine and cathinone were identified in khat extract using the gas chromatography technique. Our work provides preclinical insight into the efficacy of β-lactam-containing compounds for the attenuation of neurobehavioral changes induced by khat exposure.
... A similar SPE was used for detecting two mephedrone metabolites which are 4-methylcathinone and 4-methylephedrine. Mephedrone is the most popular synthetic cathinone in the drug market which mimics amphetamine and it is a cheap alternative for phenethylamine drugs like A, MA, MDMA, etc. [20]. Investigation on these metabolites includes cyclic and differential pulse voltammetric examination, which shows good linearity in both solutions i.e. buffer and human urine spiked by the drug. ...
Screen printing technology is a method of ink-based printing that utilizes a stencil mesh screen to create a visual pattern on a flat surface, such as plastic or silk. This process finds application in the production of screen-printed electrodes, which are utilized in electrochemical cells as part of voltammetric techniques. These electrodes offer advantages in terms of simplicity, portability, and ease of use compared to more intricate techniques. Various voltammetric methods are employed to analyze materials present in trace quantities, including drugs and explosives. By employing screen-printed electrodes in these electro-analytical techniques, it becomes possible to achieve straightforward, cost-effective, sensitive, and rapid detection of analytes with forensic significance. This highlights the significance of screen-printed electrodes in both onsite and laboratory forensic examinations.
... Compounds that are among the most popular on the current NPS market are synthetic cathinones; their mode of action involves amphetamine-like or cocaine-like stimulation. The literature on the subject contains numerous reports on the effects of cathinone derivatives and reports of overdose cases [2][3][4][5][6][7]. ...
In this paper, two cathinone derivatives, 4F-3Me-α-PVP and N-ethylheptedrone, seized on the illegal drug market in Poland, were described and characterized by various instrumental analytical methods. The compounds were characterized by electrospray ionization mass spectrometry, high-resolution mass spectrometry, gas chromatography–mass spectrometry, infrared spectroscopy, X-ray crystallography, thermogravimetric analysis, differential scanning calorimetry and nuclear magnetic resonance spectroscopy. The two tested compounds were confirmed as 1-(4-fluoro-3-methylphenyl)-2-(pyrrolidin-1-yl)pentan-1-one and N-ethyl-2-amino-1-phenylheptan-1-one hydrochlorides; both are cathinone derivatives available on the market for new psychoactive substances (NPS). The obtained analytical data should be useful for forensic and toxicological purposes in the rapid and reliable identification of compounds.
... versus 85.15 +_36.73mg/dl (20) and inconsistent with another study showed significant decrease in TG levels by 30% and 36.7% after chewing 200gm and 400gm of khat leaves [22]. ...
This study aims to investigate the association between chronic khat chewing (5 to 30 years duration) and dyslipidemia among healthy males in Al Shuaib District. One hundred participants from different villages agreed to complete the study with us. In this cross sectional study sample objects 230 males were selected randomly and divided according to ages and chewing khat duration, into four groups each (n= 20) and a control group of (n=20) non khat chewers. Data were obtained using a questionnaires and fasting blood sample collected and examined for lipid profile measurements including levels of total cholesterol TC, triglyceride TG, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C).The mean levels of TC in groups D (179.5mg/dl) and E (180mg/dl) was higher significantly than control group subjects (156mg/dl). levels of HDL decreased in khat chewers; D and E groups (44.5mg/dl and 41mg/dl) respectively compared to the control group (46.4mg/dl). On the other hand, the average LDL increased in the D and E subject groups (103.4mg/dl) and (112.4mg/dl) respectively compared with control 93.8mg/dl. The level of TG was increased in all study groups A, B, D and E having statistical significance p < 0.05 compared with control C. There was a higher dyslipidemia among subjects of khat chewing groups than non khat chewers in relation to increase of mean years of khat chewing. There is a significant association between chronic khat chewing and dyslipidemia especially the decrease in HDL-C level was the main lipid variable followed by TG level. The imbalanced lipid profile might be due to genetic factor or social dietary habits, besides wide spread use of pesticides during cultivation of khat plant which have toxicity in area of study.
... They are β-keto phenethylamine derivatives of cathinone, which is an alkaloid found in khat (Catha edulis) leaves. Cathinone is structurally identical and similar in action to amphetamine [6,7]. Synthetic cathinones are widely abused, due to their psychostimulant effects, replacing other highly consumed drugs such as 3,4methylenedioxymethamphetamine (MDMA) and cocaine [8]. ...
Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone (MDPV), are widely abused due to their psychostimulant effects. As they are chiral molecules, studies of their stereochemical stability (racemization can occur in certain temperatures and acidic/basic environments) and of their biological and/or toxicity effects (enantiomers might display different properties) are of great relevance. In this study, the liquid chromatography (LC) semi-preparative enantioresolution of MDPV was optimized to collect both enantiomers with high recovery rates and enantiomeric ratio (e.r.) values. The absolute configuration of the MDPV enantiomers was determined by electronic circular dichroism (ECD) with the aid of theoretical calculations. The first eluted enantiomer was identified as S-(-)-MDPV and the second eluted enantiomer was identified as R-(+)-MDPV. A racemization study was performed by LC-UV, showing enantiomers' stability up to 48 h at room temperature and 24 h at 37 • C. Racemization was only affected by higher temperatures. The potential enantioselectivity of MDPV in cytotoxicity and in the expression of neuroplasticity-involved proteins-brain-derived neurotrophic factor (BDNF) and cyclin-dependent kinase 5 (Cdk5)-was also evaluated using SH-SY5Y neuroblastoma cells. No enantioselectivity was observed.
... Introduction: Synthetic cathinones are a vast group of new psychoactive substances, similar to amphetamines and widely abused due to their psychostimulant effects [1]. Although they are chiral, few studies report the influence of the stereochemistry in their biological/toxicological properties [2,3]. ...
... These results suggest that mephedrone possesses anxiogenic-like properties. Published data demonstrated that synthetic cathinones, in addition to their addictive potential, often cause adverse psychiatric sequelae, including anxiety [62,63]. However, repeated psychostimulant administration induces anxiety-related behavior after 1 to 8 days of withdrawal [64][65][66]. ...
Treatment of Post-Traumatic Stress Disorder (PTSD) is complicated by the presence of drug use disorder comorbidity. Here, we examine whether conditioned fear (PTSD model) modifies the rewarding effect of mephedrone and if repeated mephedrone injections have impact on trauma-related behaviors (fear sensitization, extinction, and recall of the fear reaction). We also analyzed whether these trauma-induced changes were associated with exacerbation in metalloproteinase-9 (MMP-9) and the GluN2A and GluN2B subunits of N-methyl-D-aspartate (NMDA) glutamate receptor expression in such brain structures as the hippocampus and basolateral amygdala. Male adolescent rats underwent trauma exposure (1.5 mA footshock), followed 7 days later by a conditioned place preference training with mephedrone. Next, the post-conditioning test was performed. Fear sensitization, conditioned fear, anxiety-like behavior, extinction acquisition and relapse were then assessed to evaluate behavioral changes. MMP-9, GluN2A and GluN2B were subsequently measured. Trauma-exposed rats subjected to mephedrone treatment acquired a strong place preference and exhibited impairment in fear extinction and reinstatement. Mephedrone had no effect on trauma-induced MMP-9 level in the basolateral amygdala, but decreased it in the hippocampus. GluN2B expression was decreased in the hippocampus, but increased in the basolateral amygdala of mephedrone-treated stressed rats. These data suggest that the modification of the hippocampus and basolateral amygdala due to mephedrone use can induce fear memory impairment and drug seeking behavior in adolescent male rats.
... The aim of this study is to evaluate the profile of amphetamine derivate MTTA, a new psychoactive substance (NPS) belonging to the synthetic cathinones (SCs) group [3]. Structurally, SCs are β-keto amphetamines derivates and elicit their action on monoamines transporters [47][48][49][50]. The tested substance, MTTA, is a cathinones-like compound, but it presents a γ-amino ketonic structure [15,19]. ...
Over the last year, NPSs have been steadily on the rise in the illicit drug market. Among these, synthetic cathinones seem to become increasingly popular among young adults, mainly because of their ability to replicate the effects of traditional psychostimulant drugs, such as cocaine, MDMA and amphetamines. However, scarce data are available about the in vivo pharmaco-toxicology of these new substances. To this end, this study focused on evaluation of effects induced by repeated administration of mephtetramine (MTTA 0.1–30 mg/kg i.p.) in mice. This atypical cathinone highlighted a sensorial (inhibition of visual and acoustic reflexes) and transient physiological parameter (decrease in breath rate and temperature) change in mice. Regarding motor activity, both a dose-dependent increase (accelerod test) and biphasic effect (drag and mobility time test) have been shown. In addition, blood and urine samples have been analysed to enrich the experimental featuring of the present study with reference to evaluation of potential toxicity related to consumption of MTTA. The latter analysis has particularly revealed important changes in blood cells count and blood and urine physicochemical profile after repeated treatment with this atypical cathinone. Moreover, MTTA induced histological changes in heart, kidney and liver samples, emphasizing its potential toxicity.
... Their pharmacological, physiological, and behavioral profiles are diverse despite the shared pharmacophore. In addition to classic sympathomimetic stimulant effects, some cathinones are also known to produce hallucinogenic effects like amphetamine and methylenedioxymethamphetamine (MDMA) [10][11][12]. To comprehensively understand the unique effects of new synthetics cathinones, it is necessary to describe not only their 3D structure, but also their biological effects, which can be used to develop an effective therapy against the adverse effects. ...
Recently, the number of structural modifications of synthetic cathinones has been growing making them the second largest group of new psychoactive substances in Europe. Although they are abused because of their various psychoactive effects, some compounds from this group also serve as pharmaceuticals. Since synthetic cathinones are chiral molecules with one chiral center, their biological, toxicological, and pharmacological properties may significantly differ according to their absolute configuration and enantiomeric excess. In this study, we have synthesized two substances bearing a pharmacologically interesting trifluoromethyl group and developed a chiral liquid chromatography method using a polysaccharide chiral stationary phase to separate the corresponding enantiomers of both these drugs. Subsequently, we utilized molecular spectroscopic methods including chiroptical (electronic circular dichroism and vibrational circular dichroism) and non-polarizable (infrared and ultraviolet absorption) spectroscopies. In combination with density functional theory calculations, we have obtained stable conformers of selected enantiomers in solution and their relative abundances, which we used to simulate their spectra. The experimental and calculated data have been used to elucidate the 3D structure of the enantiomerically pure compounds and assign the absolute configuration of all prepared compounds.
... Cathinones act by increasing the concentrations of monoamines (dopamine or noradrenaline or serotonin) in the synapse through reuptake inhibition or release stimulation (depending on the compound). In small doses, cathinones generate euphoria, excitation, increased energy, empathy and selfconfidence (4)(5)(6). Side effects such as tachycardia, palpitations and hypertension are commonly reported and, with larger dose, hallucinations, delirium, acute psychosis, seizure, hyperthermia and multiorgan failure potentially leading to death have also been reported (4,(7)(8)(9). Cathinones were used as legal highs locally since the beginning of the 21st century (10), even if some of them were already synthesized a long time ago for medical purposes. ...
We report herein two cases of cathinone intoxication. The first case is about a drug addict who was admitted to the emergency room after the injection of an unknown compound. He presented with tachycardia, palpitations, mydriasis, dyspnea, dizziness, headache and nausea. After leaving the hospital against medical advice, he returned the next day with police escort, presenting aggressiveness and agitation signs. One month later, he came one more time for sleeping disorders, hallucinations and anxiety. He was finally transferred for his 21st detoxification treatment. The second case concerns a man who was wandering the streets and triedto escape when police officers called him. He confessed the snorting of n-ethylpentedrone and was admitted with severe agitation including delusion of persecution, tachycardia, mydriasis and fever. Because of his renal failure, rhabdomyolysis and metabolic acidosis, he was transferred to the ICU where he manifested worsening of the symptoms, turning into coma. He was intubated during 3 days before a complete resolution of the symptoms. A screening was performed by high resolution mass spectrometry followed by quantifications made by HPLC-DAD. In the first case, alpha-PHP was identified only during the first 2 admissions. However, as plenty of other psychotropic substances were also found, the cathinone alone could not be held directly responsible for the symptoms. In the second case, more than 2000 ng/mL of n-ethylpentedrone were found without any decrease in the next 17 hours, underlying the long half-life of this compound. Unlike the first case, symptoms could be clearly attributed to the cathinone. To conclude, cathinones can be found on the Belgian illicit drug market, with various routes of administration and clinical consequences. In these two case reports, some common points were observedinitially. However, one patient was finally able to leave the hospital without any treatment, whereas the otherwould most likely have died without intensive care.
Prodrugs are an important strategy for the development and design of therapeutic drugs. They involve the addition of an easily removable group (such as an ester) to a molecule in order to chemically protect it from metabolism, hydrolysis, or interaction with tissues. In the therapeutic drug market, prodrugs may reduce adverse effects, lead to more accurate tissue delivery, increase bioavailability and duration of effects. The same strategy has, however, been used in the illicit drug market. Internationally controlled drugs such as LSD, MDMA and benzodiazepines have been detected in the market with the addition of alkyl chain that can be removed in physiological conditions. Cyclical analogues may also be used, as is the case for 1cP‐LSD and GBL (a prodrug of GHB). Adequate detection requires increased care with extraction and analytical conditions—as the parent drugs may be formed as artifacts during these processes—and an in‐depth knowledge of metabolic pathways to avoid erroneous detection and allow for adequate identification of the drug used. Legislative updates may also be necessary to ensure prodrugs can be controlled at the same level as other illicit drugs.
This article is categorized under: Toxicology > New Psychoactive Substances
Toxicology > Drug Analysis
Toxicology > Analytical
New Psychoactive Substances are currently a serious and growing problem affecting public health worldwide. By 2022, 1184 of these substances had been identified over a period of 16 years. Within these, α-pyrrolidinohexanophenone (α-PHP) and α-pyrrolidinoisohexanophenone (α-PiHP) have emerged, two synthetic cathinones from the pyrovalerone derivates subgroup that are positional isomers of each other. Alpha-PHP appeared on the Japanese illicit drug market in 2014 and, two years later, α-PiHP was identified for the first time in China. They were placed in schedule II on the list of Psychotropic Substances under International Control in 2020 and in March 2023, respectively. Both cathinones have no therapeutic potential for medical use and therefore are abused for recreational habits, which can lead to fatalities. The most frequent adverse effects reported are cardiac, psychiatric, and neurologic, and fatal intoxications have already been described. In Portugal, their consumption and consequent seizures are more prevalent on the archipelagos, which has been aggravating the health situation. In conclusion, these types of substances are a challenge for forensic toxicology since they are easily synthesized, modified, and placed on the market. Therefore, more studies to develop analytical methods to detect them and more comprehensive legislation should be applied. Thus, this review aimed to address the legislative, physicochemical, toxicological, and analytical aspects of both substances.
Neurotoxicity induced by psychoactive substances is often accompanied by an imbalance of intracellular calcium ions. It is unclear whether calcium ions play a role in the toxicity induced by psychoactive substances. In the present study, we aimed to evaluate the occurrence of calcium dysregulation and its contribution to cytotoxicity in human neurotypic SH‐SY5Y cells challenged with a recently developed psychoactive substance 4‐methylethcathinone (4‐MEC). An increase in the intracellular calcium was detected by inductively coupled plasma atomic emission spectrometry and Fluo‐3 AM dye in SH‐SY5Y cells after being treated with 4‐MEC. The increase of intracellular Ca ²⁺ level mediated G0/G1 cell cycle arrest and ROS/endoplasmic reticulum stress‐autophagy signaling pathways to achieve the toxicity of 4‐MEC. In particular, N‐acetyl‐L‐cysteine, a classical antioxidant, was found to be a potential treatment for 4‐MEC‐induced toxicity. Taken together, our results demonstrate that an increase in intracellular calcium content is one of the mechanisms of 4‐MEC‐induced toxicity. This study provides a molecular basis for the toxicity mechanism and therapeutic intervention of psychoactive substances.
Understanding drug market dynamics and their underlying driving factors is paramount to developing effective responses to the overdose crisis in North America. This paper summarises the distinct drug market trends observed locally and internationally over the past decade to extrapolate future drug market trajectories. The emergence of fentanyl on North American street markets from 2014 onwards led to a shift of street drug use patterns. Previously perceived as contaminants, novel synthetic opioids became the drugs of choice and a trend towards higher potency was observed across various substance classes. The diversification of distribution strategies as well as the regionalisation and industrialisation of production followed basic economic principles that were heavily influenced by prosecution and policy makers. Particularly, the trend towards higher potency is likely most indicative of what to expect from future illicit drug market developments. Nitazenes and fentanyl-analogues, several times more potent than fentanyl itself, are increasingly detected in toxicological testing and have the potential of becoming the drugs of choice in the future. The dynamic of drug import and local production is less clear and influenced by a multitude of factors like precursor availability, know-how, infrastructure, and the success of local drug enforcement strategies. Drug market dynamics and the current trajectory towards ultrapotent opioids need to be recognised by legislation, enforcement, and the health care system to prepare effective responses. Without significant improvements in treatment access, the implementation of preventative approaches and early warning systems, the mortality rate will continue to increase. Furthermore, there is no mechanism in place preventing the currently North American focused overdose crisis to spread to other parts of the globe, particularly Europe. A system of oversight, research, and treatment is needed to address mortality rates of historic proportions and prevent further harm.
Advanced Pharmacy is a textbook dedicated to advanced applications in pharmacy. The book balances information by including chapters that give basic knowledge and inform readers on the latest insights in pharmaceutical science. Authored by pharmacology experts and academics, each chapter highlights current knowledge in the field, presenting research in a didactic and educational manner for academics, researchers, and students who need to understand pharmacy. Additional features of the book include chapter summaries and references for advanced readers.
Topics:
Physical Pharmacy: Covers foundations of physical pharmacy, providing a solid understanding of the subject. Preformulation Studies: examines active pharmaceutical ingredient-excipent compatibility studies, a crucial aspect of drug formulation. Medicinal Chemistry Applications: explores medicinal chemistry applications using QSAR/QSPR theory. Computer-assisted Study: explains computer-assisted studies with the example of garlic organosulfur as an antioxidant agent. Enzymes in Biocatalysis: sheds light on enzyme characteristics, kinetics, production, and applications in biocatalysis. Antifungal Agents: provides insights into antifungal agents and their significance. Polysaccharides in Drug Delivery: explores the use of naturally and chemically sulfated polysaccharides in drug delivery systems. Immunomodulatory Plant Extracts: covers the evaluation of safety and benefits of immunomodulatory plant extracts. Biofilms and Persistent Cells: examines the development, causes, and consequences of biofilms and persistent cells. Analytical Methods for Drug Analysis: focuses on the development of analytical methods for analyzing drugs of abuse using experimental design. Steric Exclusion Chromatography: discusses steric exclusion chromatography, including chromatography of polymers in aqueous solutions. Intrinsic Viscosity Methods: explores intrinsic viscosity methods in natural polymer pharmaceutical excipients. Extraction Techniques in Green Analytical Chemistry: highlight environment-firendly techniques in analytical chemistry.
Advanced Pharmacy is a comprehensive resource that bridges the gap between pharmaceutical research and practice, offering invaluable insights into the latest developments in the field. This textbook serves as an essential reference for both learners and scholars in basic and advanced courses in pharmacy and pharmaceutical science.
The consumption of novel psychoactive substances (NPS) is exceedingly prevalent in society, as these substances are sold and distributed as "legal highs." One novel synthetic cathinone emerging in the market is 1-(1,3-benzodioxol-5-yl)-2-(dimethylamino) pentan-1-one (dipentylone). The goal of this work was to study the in vivo and in vitro metabolism of dipentylone in zebrafish and human liver microsomes (HLMs) by liquid chromatography-high resolution mass spectrometry (LC-HRMS). The zebrafish and HLM samples contained 14 dipentylone metabolites, specifically 12 phase Ⅰ metabolites and 2 phase Ⅱ metabolites. The main metabolic pathways included monohydroxylation (M1 and M2), N-dealkylation (M3), hydroxylation of the aromatic ring and dealkoxylation of M3 (M4), O-dealkylation (M5), N-dealkylation of M5 (M6), reduction of carboxide (M7), monohydroxylation of M5 (M8), dehydrogenation (M9), dealkoxylation (M10), N-dealkylation of M10 (M11), dealkoxylation of M9 (M12), glucuronidation of M5 (M13), and sulfation (M14). The monohydroxylated metabolite (M2) can be recommended as metabolic markers for dipentylone. This study is the first to identify a target compound for monitoring the abuse of dipentylone and to determine the essential chemical structure of the metabolites for further toxicological research.
The binding affinity to human serum albumin (HSA) of a series of fourteen synthetic cathinones, new psychoactive substances widely abused, was investigated by high-performance affinity chromatography (HPAC). Zonal elution experiments were conducted to measure the retention times of each synthetic cathinone on an HSA column, which enabled the calculation of the percentage of the drug bound. For some synthetic cathinones, enantioselectivity on HSA was found. To gather information on the HSA binding sites and better understand the chiral recognition mechanisms, enantioresolution of selected cathinones was carried out at a milligram scale through liquid chromatography (LC) with carbamate polysaccharide-based columns. This work was followed by zonal displacement chromatography using known competitors with specific binding sites on HSA, namely (S)-ibuprofen and warfarin. Competition was observed between the tested drugs and both competitors (except for pentedrone with warfarin), which is consistent with an allosteric competition involving a non-cooperative binding mechanism.
Objective:
To identify risk factors and predictors of the development of psychotic disorders in patients who used synthetic cathinones (SKat).
Material and methods:
The study included 176 patients who used SKat, which was toxicologically confirmed. One hundred and eleven (63.1%) were male and 65 (36.9%) were female. The median age was 27 years (22-32 (Q1-Q3)). Patients were divided into main and control groups depending on the presence of a psychotic disorder. The main group (those who developed psychosis) consisted of 98 patients, the control groupincluded 78 participants. Clinical-psychopathological, parametric and statistical methods were performed to study predictors and risk factors for the development of psychotic disorders associated with the use of SKat.
Results:
The study established factors influencing the incidence of psychosis. Older patients were more likely to develop psychosis (p=0.002). Patients who used SKat for more than 21 consecutive days developed psychoses more often (p=0.048). The use of α-pvp (α-pyrrolidinovalerophenone, alpha-pvp) more often led to the development of psychosis (p<0.001). Patients undergoing rehabilitation were less likely to experience the development of psychosis (p=0.009). The resulting regression model is statistically significant (p<0.001). Based on the value of the Nigelkirk coefficient of determination, the model explains 30.9% of the observed group variance. It has been established that the combination of the following factors increases the chances of developing psychosis: female gender, age, duration of daily use, the presence of signs of mental infantilism, fear of the dark in childhood. In turn, the experience of undergoing rehabilitation and any pathology of the mother's pregnancy reduces the risk of psychosis.
Conclusion:
The results are consistent with other studies of substance-induced psychoses. The observed patterns demonstrate that this is a special group of disorders that requires the attention of specialists. The results allow us to outline the field for further study, and may also be useful in the development of therapeutic and preventive recommendations.
Background:
Slamming has been increasing internationally for ten years, mostly among men who have sex with men. Slamming consists of injecting psychostimulants (including new psychoactive substances-NPS) intravenously to increase sexual performance.
Objective:
The objective of our work was to analyse drug-drug interactions related to slamming.
Methods:
Drawing upon a reported case of a slam session describing hour by hour the intake of substances, we performed a drug-interaction analysis using international references and a comprehensive literature review. High doses of sildenafil, GBL and 3-MMC were reported during the 40-hour session described. The specific drug-interaction research was performed using 9 references and 65 of the 209 records identified in the literature review.
Results:
Pharmacological data regarding nonmedicated substances were scarce. Regarding pharmacodynamics, the risk was high at the cardiovascular level and was related to the vasodilatation effect of sildenafil and the adrenergic and serotoninergic properties of stimulants; this risk may increase with usual treatment (involving other vasodilators or central depressants). Regarding pharmacokinetics, the major interactions concerned metabolism by CYP3A4 and CYP2C9, leading to interactions, particularly with HIV medication.
Conclusion:
This innovative work provides pharmacological information on drugs that are commonly used in slamming, allowing the development of effective medical-management protocols and the provision of risk-reduction counselling.
One of the new synthetic cathinones that has a high tendency to replace ecstasy and other established synthetic drugs is N- ethylpentylone, (NEP), due to its high potency, stimulative, hedonic and hallucinatory effects. In order to examine the interactions of NEP, the apparent molar quantities, thermal expansion coefficient, the apparent molar volume at infinite dilution and the limiting apparent molar expansibility were calculated from the experimental measurements of the density of NEP aqueous solutions in different temperature and molality ranges, from T = (293.15 to 313.15) K and from m = (0.05898 to 0.0977) mol·kg –1 , respectively. The taste of NEP was estimated by calculated values of apparent specific molar volume at infinite dilution and it was concluded that its taste in aqueous solutions is bitter. Also, using the spectrofluorimetric technique, an intermolecular deactivation of in situ formed ethidium bromide (EB) complex with DNA (EB-DNA) was investigated in the presence of NEP. Obtained results indicated good affinity and efficiency of NEP to substitute EB from the EB-DNA complex via intercalation mode. Using molecular docking, it was concluded that the binding energy obtained for NEP indicates its higher affinity to interact with DNA, compared to methamphetamine and amphetamine, but lower compared to ecstasy. The affinity of NEP to bind to bovine serum albumin (BSA) was also investigated and discussed. It is shown that NEP could be efficiently transported and distributed through the blood and cells.
The psychoactive shrub Catha edulis (khat or qat) has been used by humans for centuries due to the psychoactive properties of its endogenous alkaloid cathinone. In recent years, synthetic derivatives of cathinone, herein referred to as synthetic cathinones and colloquially referred to as “bath salts,” have infiltrated drug markets worldwide. As a result, evidence of abuse, dependence, toxicity, and adverse cognitive effects has emerged. In this chapter, we will provide a brief overview of synthetic cathinones and their neuropharmacological mechanisms of action. Next, we will review the adverse cognitive effects of acute and chronic exposure to synthetic cathinones in both animals and humans. Finally, we will provide a hypothetic model of potential mechanisms, at the level of both cellular toxicity and neuroinflammation, that may underlie the neurocognitive dysfunction induced by this class of abused substances.
Background:
Synthetic cathinones are the most used novel psychoactive substances in Taiwan because they exhibit psychoactive effects similar to those of methamphetamine, inducing acute psychosis, violence, and self-harm. However, the differences in the clinical characteristics of patients with synthetic cathinone and methamphetamine intoxication admitted to psychiatric emergency departments (EDs) remain unclear.
Methods:
This study recruited patients with stimulant intoxication who were admitted to a psychiatric ED from April 2019 to May 2020. Sociodemographic, lifestyle, and psychopathological data were collected through face-to-face interviews and evaluated. Immunoassay tests and liquid chromatography-quadrupole time-of-flight mass spectrometry were performed to detect substances in urine specimens. The patients were matched by sex and age (in 5-year intervals). The associations between the 2 groups and physical complications were analyzed through logistic regression.
Results:
Twenty-four patients with synthetic cathinone intoxication were identified and matched with 48 patients with methamphetamine intoxication. The 2 groups exhibited similar clinical severity of psychotic symptoms and high risks of violence and self-harm. Both groups were predominated by unmarried patients, unemployed patients, and habitual smokers and drinkers. However, family histories of substance use and criminal records were less prevalent among the patients with synthetic cathinone intoxication, but they had a higher rate of physical complications (odds ratio, 8.55; 95% confidence interval, 2.15-34.03), compared with patients with methamphetamine intoxication.
Conclusions:
Compared with patients intoxicated with methamphetamine, those intoxicated with synthetic cathinones may have similar tendencies toward psychosis, violence, and self-harm but higher risks of physical complications, which are prioritized in psychiatric EDs.
Drug misuse and dependence is an ever evolving field of study, which has exploded over recent years owing to the advent of the internet. Due to the ever-growing number of young people using drugs recreationally and the privatisation of drug screening and detection services, there is the need to disseminate evidence-based information concerning the technology and methods available for studying this expanding field.
Detection of Drug Misuse describes the current state-of-the-art techniques used for identifying and confirming drug misuse as well as recent advances in biomarkers, instrumentation and analysis methodology. The title discusses both recreational and designer drugs, including non-addictive and addictive drugs.
This book is a useful and fascinating resource for healthcare professionals working in the field of drug misuse as well as academics and postgraduates researching within analytical, chromatography, medicinal and pharmaceutical chemistry; drug metabolism; addiction science; and forensic toxicology, science and medicine.
New designer drugs, access to databases, and changing availability of samples for analysis have changed the face of modern forensic toxicology in recent years. Forensic Toxicology: Drug Use and Misuse brings together the latest information direct from experts in each sub-field of the discipline providing a broad overview of current thinking and the most innovative approaches to case studies.
The text begins with an in-depth discussion of pharmacoepidemiology, including information on the value of nationwide databases in forensic toxicology. The use and abuse of drugs in driving, sport and the workplace are then discussed by industry experts who are conducting case work in their field. Not only are new drug groups discussed (NPS), but also their constantly changing impact on drug legislation. Synthetic cannabinoids, khat and mephodrone are discussed in detail. Following a section devoted to legislation and defence, readers will find comprehensive chapters covering sample choice reflecting the increasing use of hair and oral fluid, and also the less commonly used sweat and nail analysis. New and old case examples are compared and contrasted in the final part of the book, which will enable readers to understand how drugs impact on each other and how the interpretative outcome of a case are dependent on many aspects.
From use of pharmaceutical drugs in a clinical setting, through smart drugs to new psychoactive drugs, this book documents the wide range in which drugs today are abused. This book will be an essential resource for postgraduate students in forensic toxicology, and for researchers in forensic toxicology laboratories who need the latest data and knowledge.
The amphetamine‐type stimulants (ATS) adulteration is currently a common phenomenon that endangers the health of consumers. Among the most common adulterants are new psychoactive substances (NPS), such as synthetic cathinones. This development demands new, low‐cost, and simple detection strategies. In this work, we present, for the first time, the electrochemical detection of two NPSs, the amphetamine 3,4‐methylenedioxymethamphetamine (MDMA) and the synthetic cathinone α‐pyrrolidinopentiophenone (α‐PVP), using an electrochemical biosensor based on cytochrome P450 2D6 (CYP2D6). This biosensor was constructed by electrochemical reduction of the 4‐nitrobenzenediazonium salt on a carbon screen‐printed electrode (C‐SPE), with subsequent reduction of the nitro group into amines, and finally covalent binding with the CYP2D6 enzyme. The biosensor voltammetric response of the molecules studied allowed reaching limits of detection (LOD) of 0.0017 and 0.0022 μg/mL, and limits of quantification (LOQ) of 0.0059 and 0.0076 μg/mL for MDMA and α‐PVP, respectively.
The dopamine transporter (DAT) mediates reuptake of dopamine from the synaptic cleft into the presynaptic terminus and plays a critical role in maintaining the normal function of dopaminergic neurons. DAT is the major target of widely abused psychostimulant drugs, including cocaine and amphetamine. DAT also figures into disease states, and it is a target for therapeutic drugs. It is known that cathinone and methcathinone, β-keto analogs of amphetamine and methamphetamine, respectively, produce pharmacological actions similar to amphetamine. Cathinone and methcathinone analogs are recently gaining in popularity on the clandestine market (e.g. ‘bath salts’). Cathinone and methcathinone analogs as well as their amphetamine and methamphetamine counterparts were synthesized and examined at the hDAT expressed in Xenopus oocytes. One of the two major constituents of ‘bath salts’ (i.e., mephedrone) produced an electrophysiological signature similar to the dopamine releasing agent S(+)-amphetamine while the other major constituent (i.e., MDPV) produced an electrophysiological signature similar to the dopamine re-uptake inhibitor cocaine.
Methylone is a member of the designer drug class known as synthetic cathinones which have become increasingly popular drugs of abuse in recent years. Commonly referred to as "bath salts", these amphetamine-like compounds are sold as "legal" alternatives to illicit drugs such as cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Following their dramatic rise in popularity along with numerous reports of toxicity and death, several of these drugs were classified as Schedule I drugs in the United States in 2012. Despite these bans, these drugs and other new structurally similar analogues continue to be abused. Currently, however, it is unknown whether these compounds possess the potential for compulsive use and addiction. The present study sought to determine the relative abuse liability of methylone by employing intravenous self-administration (IVSA) and intracranial self-stimulation (ICSS) paradigms in rats. We demonstrate that methylone (0.05, 0.1, 0.2, and 0.5 mg/kg/infusion) dose-dependently functions as a reinforcer, and that there is a significant positive relationship between methylone dose and reinforcer efficacy. Furthermore, responding during short access sessions (ShA, 2 hr/day) appeared more robust than previous IVSA studies with MDMA. However, unlike previous findings with abused stimulants such as cocaine or methamphetamine, long access sessions (LgA, 6 hr/day) did not lead to escalated drug intake or increased reinforcer efficacy. Finally, methylone produced a dose-dependent, but statistically non-significant, trend towards reductions in ICSS thresholds. Together these results reveal that methylone may possess an addiction potential similar to or greater than MDMA, yet patterns of self-administration and effects on brain reward function suggest that this drug may have a lower potential for abuse and compulsive use than prototypical psychostimulants.
Rationale
Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine.
Objective
The major aims were to investigate the pharmacokinetics and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model.
Methods
Mephedrone was administered to male Sprague–Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180–240 min.
Results
Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α = 10.23 h−1, β = 1.86 h−1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59 ± 3.67 %. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85 ± 0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic–pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect.
Conclusions
We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude, and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.
Recently there has been a dramatic rise in the abuse of so-called “bath salts” products that are purchased as legal alternatives to illicit drugs like cocaine and 3,4-methylenedioxymethamphetamine (MDMA). Baths salts contain one or more synthetic derivatives of the naturally-occurring stimulant cathinone. Low doses of bath salts produce euphoria and increase alertness, but high doses or chronic use can cause serious adverse effects such as hallucinations, delirium, hyperthermia and tachycardia. Owing to the risks posed by bath salts, the governments of many countries have made certain cathinones illegal, namely: 4-methylmethcathinone (mephedrone), 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV). Similar to other psychomotor stimulants, synthetic cathinones target plasma membrane transporters for dopamine (i.e., DAT), norepinephrine (i.e., NET) and serotonin (i.e, SERT). Mephedrone and methylone act as non-selective transporter substrates, thereby stimulating non-exocytotic release of dopamine, norepinephrine and serotonin. By contrast, MDPV acts as a potent blocker at DAT and NET, with little effect at SERT. Administration of mephedrone or methylone to rats increases extracellular concentrations of dopamine and serotonin in the brain, analogous to the effects of MDMA. Not surprisingly, synthetic cathinones elicit locomotor activation in rodents. Stimulation of dopamine transmission by synthetic cathinones predicts a high potential for addiction and may underlie clinical adverse effects. As popular synthetic cathinones are rendered illegal, new replacement cathinones are appearing in the marketplace. More research on the pharmacology and toxicology of abused cathinones is needed to inform public health policy and develop strategies for treating medical consequence of bath salts abuse.
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.
Catha edulis (khat) is a plant grown in the countries around the Red Sea and on the eastern coast of Africa. Its leaves are chewed by the local people for their stimulant action. Its principal active constituents are cathinone and cathine, which have sympathomimetic actions. Migration of Africans from these countries has spread the habit of khat chewing to the West. Chewing khat has a number of important psychological and physical sequelae. 'Khat-related' psychosis is very similar to that seen following use of amphetamines.
This review summarizes technical improvements in the forensic analysis for conjugate metabolites of metham- phetamine (MA), 3,4-methylenedioxymethamphetamine (MDMA) and their designer drugs. The improvements include the establishments of liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS) in com- bination with the pretreatment methods. The direct determination techniques for the conjugates proved to be effec- tive in rapidly and accurately examining many biological specimens without annoying hydrolysis. The metabolism of MA and MDMA, with attention to the phase II metabolism o ft he major hydroxy metabolites, is also discussed based on concentration data in biological specimens obtained from drug abusers.
The drug 4-methylmethcathinone (4-MMC; aka, mephedrone, MMCAT, “plant food”, “bath salts”) is a recent addition to the list of popular recreational psychomotor-stimulant compounds. Relatively little information about this drug is available in the scientific literature, but popular media reports have driven recent drug control actions in the UK and several US States. Online user reports of subjective similarity to 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) prompted the current investigation of the thermoregulatory and locomotor effects of 4-MMC. Male Wistar and Sprague-Dawley rats were monitored after subcutaneous administration of 4-MMC (1–10 mg/kg ) using an implantable radiotelemetry system under conditions of low (23°C) and high (27°C) ambient temperature. A reliable reduction of body temperature was produced by 4-MMC in Wistar rats at 23°C or 27°C with only minimal effect in Sprague-Dawley rats. Increased locomotor activity was observed after 4-MMC administration in both strains with significantly more activity produced in the Sprague-Dawley strain. The 10 mg/kg s.c. dose evoked greater increase in extracellular serotonin, compared with dopamine, in the nucleus accumbens. Follow-up studies confirmed that the degree of locomotor stimulation produced by 10 mg/kg 4-MMC was nearly identical to that produced by 1 mg/kg d-methamphetamine in each strain. Furthermore, hypothermia produced by the serotonin 1A/7 receptor agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) was similar in each strain. These results show that the cathinone analog 4-MMC exhibits thermoregulatory and locomotor properties that are distinct from those established for methamphetamine or MDMA in prior work, despite recent evidence of neuropharmacological similarity with MDMA.
Aims and method
Mephedrone is a cathinone with amphetamine-like stimulant effects, and is a commonly used recreational drug. The adverse effects of mephedrone use have not been extensively studied. All individuals who self-presented between January and June 2010 to the emergency departments and acute mental health services in Edinburgh and Falkirk with adverse effects of self-reported mephedrone use were identified.
Results
Twenty cases were identified and analysed. Severe agitation was the most common presenting problem (70%), with 40% of individuals developing psychotic symptoms and a further 20% reporting low mood and suicidality. One person died by suicide.
Clinical implications
Mephedrone can produce amphetamine-like adverse psychological intoxication effects, particularly in those with a history of mental illness. Clinicians should consider advising patients on the adverse effects of mephedrone, where relevant.
The regulation and control of psychoactive substances and their precursors is constantly counteracted by the imagination, inventiveness, experimentation and targeted research that consumers/manufacturers use in order to elude the laws, which during the last few years has led to a surge in the marketing and use of these products in the context of a missing or unclear legal framework. We are witnessing an explosion in the use of some products and substances which are either new intoxicants, or have been considered benign until recently (such is the case with numerous species of plants). The legal and medical systems are currently facing conceptual problems: how to define or characterise the product of interest (considering its ubiquitous availability and marketing forms), which of its active principles should be controlled (including by-products created by spicing the basic product), which are the applicable criminal, civil or commercial laws, how to control the "rerouting" of pharmaceutical/parapharmaceutical remedies, common drugs, nutritional supplements, exotic aromas, fertilizers or spices - the so-called unconventional intoxicants. The limitations of scientific knowledge, the novelty of various psychoactive blends, the appearance of new classes of substances, the mix with different plants etc. are major impediments for the increase in the reaction time and consequently for an efficient control by the authorities. In order to provide evidence for intoxication, a certain flexibility is needed for the on-site forensic investigation, analysis of the corpus delicti (toxicology and botanics), and the clinical examination, while toxicological detection may be of support in the context of technical-scientific difficulties. Driving under influence thus becomes a challenge for the traffic safety and for the authorities or persons authorised to conduct the inquiry and limit the phenomenon. The present article aims to provide a synthesis of the current scientific knowledge on legal highs and an overview of the limitative, but also promising toxicological issues which are needed for the description of the phenomenon.
Over the past few years, the phenomenon of new designer drugs has attracted much attention. Synthetic cannabinoids and cathinones are the two main classes of these drugs. Both are potent drugs of abuse, and several cases of severe toxicity and deaths are reported. The present work is based on a systematic review of studies that have assessed the market and prevalence of synthetic cannabinoids and cathinones, and integrates pharmacological, sociological, and epidemiological aspects of these two groups of emerging synthetic drugs. The review reflects that the Internet has made synthetic cannabinoids and cathinones widely available. Furthermore, aggressive and widespread marketing, as well as the low price level of these drugs, their juridical status and their lack of detection on standard drug tests may serve as major motivations for drug use. The number of prevalence studies is small and derived from a limited number of countries. In spite of the many methodological shortcomings, some conclusions may be cautiously drawn. Taken together, the results point toward higher prevalence of use for synthetic cathinones than for synthetic cannabinoids. In the general population, the prevalence of use of synthetic cathinones is reported to be around 4% compared to figures lower than 1% for synthetic cannabinoids. Among students, the prevalence varies from 1-20% for synthetic cathinones and 2-10% for synthetic cannabinoids. Among groups with high rates of drug use, the prevalence varies between 4% to more than 60% for synthetic cathinones and around 10% for synthetic cannabinoids.
Copyright © 2013 Central Police University.
To date, the Toxicology Section of the Montgomery County Coroner's Office/Miami Valley Regional Crime Laboratory has identified six synthetic cathinones, commonly found in bath salt products, in 43 cases. Thirty-two cases will be reviewed here, including all of the postmortem cases, all of the human performance cases that had blood specimens submitted, and one urine-only human performance case. The following compounds have been confirmed: 3,4-methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), pyrovalerone, pentylone, alpha-pyrrolidinopentiophenone (alpha-PVP) and methedrone. The method also screens for mephedrone, butylone and 3-fluoromethcathinone. Case demographics show 42 white males and females ranging in age from 19 to 53 years. The remaining case was that of a 34-year-old Hispanic male. The 43 cases represent 17 driving under the influence, two domestic violence, four suicides, 12 overdoses, six accidents, one drug-facilitated assault and one homicide. Data will be presented on the distribution of some of these cathinones in various matrices. After review, blood concentration does not appear to predict outcome regarding fatalities or impairment. The highest MDPV concentration occurred in a suicide by hanging and the highest methylone concentration was in a driver. The confirmation method is a liquid-liquid extraction with detection by liquid chromatography triple quadrupole mass spectrometry using electrospray ionization in multiple reaction monitoring mode.
We present a case of a potentially lethal ingestion of "Bath Salts." After presentation, we briefly review the epidemiology and pathology of "bath salts" ingestion.
In recent years, synthetic analogues of naturally occurring cathinone have emerged as psychostimulant-like drugs of abuse in commercial 'bath salt' preparations. 3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of these illicit products, and its structural similarities to the more well-known drugs of abuse 3,4-methylenedioxymethamphetamine (MDMA), and methamphetamine (METH) suggest that it may have similar in vivo effects to these substances. In these studies, adult male NIH Swiss mice were trained to discriminate 0.3 mg/kg MDPV from saline, and the interoceptive effects of a range of substitution doses of MDPV, MDMA, and METH were then assessed. In separate groups of mice, surgically implanted radiotelemetry probes simultaneously monitored thermoregulatory and locomotor responses to various doses of MDPV and MDMA, as a function of ambient temperature. We found that mice reliably discriminated the MDPV training dose from saline and that cumulative doses of MDPV, MDMA, and METH fully substituted for the MDPV training stimulus. All three drugs had similar ED(50) values in this procedure. Stimulation of motor activity was observed following administration of a wide range of MDPV doses (1-30 mg/kg), and the warm ambient temperature potentiated motor activity and elicited profound stereotypy and self-injurious behavior at 30 mg/kg. In contrast, MDPV-induced hyperthermic effects were observed in only the warm ambient environment. This pattern of effects is in sharp contrast to MDMA, where ambient temperature interacts with thermoregulation, but not locomotor activity. These studies suggest that although the interoceptive effects of MDPV are similar to those of MDMA and METH, direct effects on thermoregulatory processes and locomotor activity are likely mediated by different mechanisms than those of MDMA.Neuropsychopharmacology advance online publication, 5 December 2012; doi:10.1038/npp.2012.233.
Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its reuptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20 or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (4 injections of 2.5 or 5.0 mg/kg at 2 hr intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and MDMA on DA nerve endings. In contrast, nomifensine protected against methamphetamine-induced neurotoxicity. Because mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity. © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12114.
Synthetic cathinones are synthetic derivatives of the natural cathinone, one of the psychoactive compounds present in Catha edulis (khat). There are at least 12 different types of synthetic cathinones, with mephedrone and 3,4-methylendioxypyrovalerone (MDPV) being the most commonly used by the purchasers. The legal control of these substances is especially difficult because when a specific compound is banned, a new slightly modified chemical variant is introduced into the market. It has been described that patients after taking synthetic cathinones may show signs and symptoms of the sympathicomimetic toxidrome, including agitation, psychosis, tachycardia, hypertension, and seizures. Furthermore, some cases of deaths related to their consumption have also been reported. Nowadays, there is no established treatment protocol for the clinical management of these intoxications. Because of this, we have developed some recommendations that may be useful to determine the treatment of these patients.
Objectives
To show the subjective and cardiovascular effects of khat leaves having a standardized content of cathinone.Background
The main effect of khat is an increase of energy and alertness. This effect is thought to be attributable to the phenylalkylamine cathinone, but no controlled clinical trials have been published.DesignThe design was balanced and double blind. Six drug-naïve volunteers received a single dose of khat corresponding to 0.8 mg/kg body weight, as well as alkaloid-free khat as a placebo. Psychologic effects were evaluated by the Addiction Research Center Inventory (ARCI) and visual analog scales. Physiologic measures were systolic blood pressure, diastolic blood pressure, and heart rate. Plasma concentrations of cathinone and its metabolites norephedrine and R,R-(—) norpseudoephedrine were determined by HPLC.ResultsMaximal plasma concentrations of cathinone (127 ± 53 [SD] ng/ml) were attained after 127 ± 30 minutes. The area under the plasma concentration—time curve from 0 to 9 hours was 415 ± 207 ng/ml · hr, and the terminal elimination half-life was 260 ± 102 minutes. An effect of khat was observed in the ARCI scales Abuse Potential (p < 0.01), Motor Stimulation (p < 0.02), Amphetamine-Like Effect (p < 0.005), and Stimulation-Euphoria (p < 0.005), as well as in the visual analog scales Excited-Calm (p < 0.001) and Energetic-Lethargic (p < 0.001).Conclusions
Our results provide objective evidence for the amphetamine-like stimulatory effects of khat leaves. These effects were closely similar to those observed after cathinone, 0.5 mg/kg body weight, although peak plasma concentrations of cathinone after khat were delayed.Clinical Pharmacology and Therapeutics (1994) 55, 556-562; doi:10.1038/clpt.1994.69
The nonmedical use of ‘designer’ cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study.Keywords: dopamine; MDMA; mesolimbic; microdialysis; serotonin (5-HT); transporters
This Final Order is issued by the Administrator of the Drug Enforcement Administration (DEA) to extend the temporary scheduling of methylone (3,4-methylenedioxy-N-methylcathinone) including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible, into Schedule I of the Controlled Substances Act (CSA). The temporary scheduling of methylone is due to expire on October 20, 2012. This document will extend the temporary scheduling of methylone to April 20, 2013, or until rulemaking proceedings are completed, whichever occurs first.
R,S-4'-Methoxy-alpha-pyrrolidinopropiophenone (MOPPP) is a new designer drug with assumed amphetamine-like effects, which has appeared on the illicit drug market. The aim of this study was to identify the MOPPP metabolites using solid-phase extraction, ethylation or acetylation as well as to develop a toxicological detection procedure in urine using solid-phase extraction, trimethylsilylation and GC-MS. Analysis of urine samples of rats treated with MOPPP revealed that MOPPP [limit of detection (S/N 3) was 100 ng/ml] was completely metabolized by demethylation of the methoxy group, hydroxylation of the pyrrolidine ring with subsequent dehydrogenation to the corresponding lactam and/or oxidative desamination to the corresponding diketo compounds. To some extent, the demethylated MOPPP metabolites were hydroxylated with partial subsequent methylation in position 3'. The hydroxy groups were found to be partly conjugated. Based on these data, MOPPP could be detected in urine via its metabolites by full-scan GC-MS using MS for screening and library search for identification by comparison of the spectra with reference spectra.
The Administrator of the Drug Enforcement Administration (DEA) is issuing this final order to temporarily schedule three synthetic cathinones under the Controlled Substances Act (CSA) pursuant to the temporary scheduling provisions of 21 U.S.C. 811(h). The substances are 4-methyl-N-methylcathinone (mephedrone), 3,4-methylenedioxy-N-methylcathinone (methylone), and 3,4-methylenedioxypyrovalerone (MDPV). This action is based on a finding by the Administrator that the placement of these synthetic cathinones and their salts, isomers, and salts of isomers into Schedule I of the CSA is necessary to avoid an imminent hazard to the public safety. As a result of this order, the full effect of the CSA and its implementing regulations including criminal, civil and administrative penalties, sanctions and regulatory controls of Schedule I substances will be imposed on the manufacture, distribution, possession, importation, and exportation of these synthetic cathinones.
The new recreational designer drugs known as “bath salts” are synthetic cathinones (e.g., mephedrone, 3,4-methylenedioxypyrovalerone, methylone) that are being abused as stimulants. Bath salts have similar effects as amphetamine, cocaine, and MDMA (3,4-methylenedioxymethamphetamine, also known as ecstasy). Cathinone is a naturally occurring phenylalkylamine alkaloid present in the khat plant that has been used for centuries, but in Western countries, they are primary used by “young clubbers.” In this review, the pharmacology and neurotoxicity of bath salts will be discussed and the prevalence and pattern of bath salt use will be presented. The U.S. Poison Control Center received an increasing number of calls regarding bath salt intoxication in 2011, which led to an emergency temporary ban in September 2011. Despite the ban, the use of bath salts has continued. Multiple reports have described the clinical features of bath salt intoxication and withdrawal symptoms, as well as the potential for abuse and the development of dependence. There are reports of bath salts causing hallucinations, delirium, and psychosis. For patients presenting with bath salt intoxication, management includes using medications for behavioral control and other symptomatic support. In this review, we will report the use of bath salts in a patient with a history of schizophrenia and comorbid methamphetamine dependence. His clinical course will be discussed. In order to prevent the further abuse of bath salts, we need to encourage the continuing ban on the sale of bath salts and also educate both clinicians and patients about the risks of using such drugs.
Khat is a bushy plant whose leaves are chewed for their stimulant effect. Although khat has been a boon to the local economy, a suspected disadvantage is that there has been a decrease of land dedicated to rice and vegetable crops. Concerns about khat stem from genuine issues of food security but also from a moral panic targeted at this recreational drug crop. The major finding is that a decrease in vegetable production has not been primarily caused by khat but instead by a decline in the market for vegetables and decayed local infrastructure supporting vegetable production and transport. We also found that most farmers prefer to grow food crops alongside their khat, and many grow khat on marginal lands. Furthermore, khat helps many individual farmers increase food security because of the income it provides. The general significance is to point out that drug crops have a unique place in discussions of food security because of both the high amount that buyers are willing to pay and because of public condemnation of recreational drugs.
Cathinone-derived designer drugs have recently grown to be popular as drugs of abuse. 3,4-Dimethylmethcathinone (DMMC) has recently been abused as one of the alternatives to controlled cathinones. In the present study, DMMC and its major metabolites, 3,4-dimethylcathinone (DMC), 1-(3,4-dimethylphenyl)-2-methylaminopropan-1-ol (β-OH-DMMC, diastereomers), and 2-amino-1-(3,4-dimethylphenyl)propan-1-ol (β-OH-DMC, diastereomers), have been identified and quantified in a DMMC user’s urine by gas chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry using newly synthesized authentic standards. Other putative metabolites including oxidative metabolites of the xylyl group and conjugated metabolites have also been detected in urine. The identified and putative phase I metabolites indicated that the metabolic pathways of DMMC include its reduction of the ketone group to the corresponding alcohols, N-demethylation to the primary amine, oxidation of the xylyl group to the corresponding alcohol and carboxylate forms, and combination of these steps. Concentrations of the identified metabolites were found to increase slightly after enzymatic hydrolysis, suggesting that these compounds are partially metabolized to the respective conjugates.
Recreational drug use patterns change constantly, making it imperative that clinicians continuously update their knowledge about current trends of use and abuse. Particularly challenging are substances that have been described as nontraditional, emerging, and Web based, which have increased significantly in the last 2 years. This report reviews the epidemiology, pharmacology, clinical presentation, and toxicity as well as recommended management for 2 classes of emerging substances of abuse: herbal marijuana alternatives (eg, synthetic cannabinoids) and “bath salts” (eg, substituted cathinones). A brief review of the development of the regulation of these substances highlights the challenges associated with surveillance and subsequent enforcement of laws for emerging nontraditional substances of abuse.
Consumption of khat leaves produces symptoms that are similar to those caused by amphetamine. The experiments reported in the following describe the effect of the two khat alkaloids (−)-cathinone and (+)-norpseudoephedrine at the cellular level. Both were shown to induce release from physiological catecholamine storage sites. Peripheral noradrenaline sites (rabbit heart) were observed to be more sensitive than CNS dopamine sites (rat nucleus accumbens). In the latter organ, which is believed to be involved in amphetamine hypermotility, (−)-cathinone was considerably more potent than (+)-norpseudoephedrine.
A 31-year-old man purchased the legal high Energy-1 (NRG-1) over the internet; this was advertised as containing the compound naphthylpyrovalerone (NPV), which at the time was currently legally available in the UK. He ingested 1 g of this substance and developed a prolonged high associated with palpitations, sweating and insomnia. Analysis of both the powder and serum samples from the patient demonstrated that he ingested two classified recreational drugs β-keto-N-methylbenzodioxolylpropylamine (butylone) and methylenedioxypyrovalerone (MDPV) rather than the legal substance NPV. Users of legal highs need to be aware that legal highs purchased over the internet may contain illegal substances and therefore they may be liable for prosecution if found in possession of these substances. Future educational campaigns aimed at recreational drug and legal high users should include reference to the potential legal implications of buying these substances.
Mephedrone (MMC) is a relatively new recreational drug that has rapidly increased in popularity in recent years. This study explored the characteristics of intravenous MMC self-administration in the rat, with methamphetamine (METH) used as a comparator drug. Male Sprague-Dawley rats were trained to nose poke for intravenous MMC or METH in daily 2 h sessions over a 10 d acquisition period. Dose-response functions were then established under fixed- and progressive-ratio (FR and PR) schedules over three subsequent weeks of testing. Brains were analyzed ex vivo for striatal serotonin (5-HT) and dopamine (DA) levels and metabolites, while autoradiography assessed changes in the regional density of 5-HT and serotonin transporter (SERT) and DA transporter (DAT) and induction of the inflammation marker translocator protein (TSPO). Results showed that MMC was readily and vigorously self-administered via the intravenous route. Under a FR1 schedule, peak responding for MMC was obtained at 0.1 mg/kg/infusion, versus 0.01 mg/kg/infusion for METH. Break points under a PR schedule peaked at 1 mg/kg/infusion MMC versus 0.3 mg/kg/infusion for METH. Final intakes of MMC were 31.3 mg/kg/d compared to 4 mg/kg/d for METH. Rats self-administering MMC, but not METH, gained weight at a slower rate than control rats. METH, but not MMC, self-administration elevated TSPO receptor density in the nucleus accumbens and hippocampus, while MMC, but not METH, self-administration decreased striatal 5-hydroxyindolacetic acid (5-HIAA) concentrations. In summary, MMC supported high levels of self-administration, matching or exceeding those previously reported with other drugs of abuse.
In this report, we describe a case of intranasal "bath salts"-associated psychosis. Symptoms developed during a 3-week binge and were potentially exacerbated by oral diphenhydramine taken for insomnia. The clinical case conference includes expert discussion from 3 disciplines: emergency medicine toxicology, behavioral pharmacology, and addiction medicine. It is hoped that the discussion will provide insight into the clinical aspects and challenges of addressing acute substituted cathinone toxicity, including acute psychosis, a major adverse effect of bath salts consumption.
Introduction:
Methylone (3,4-methylenedioxymethcathinone) is a new psychoactive substance and an active ingredient of "legal highs" or "bath salts". We studied the pharmacokinetics and locomotor activity of methylone in rats at doses equivalent to those used in humans.
Material and methods:
Methylone was administered to male Sprague-Dawley rats intravenously (10mg/kg) and orally (15 and 30 mg/kg). Plasma concentrations and metabolites were characterized by LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min.
Results:
Oral administration of methylone induced a dose-dependent increase in locomotor activity in rats. The plasma concentrations after i.v. administration were described by a two-compartment model with distribution and terminal elimination phases of α=1.95 h(-1) and β=0.72 h(-1). For oral administration, peak methylone concentrations were achieved between 0.5 and 1h and fitted to a flip-flop model. Absolute bioavailability was about 80% and the percentage of methylone protein binding was of 30%. A relationship between methylone brain levels and free plasma concentration yielded a ratio of 1.42 ± 0.06, indicating access to the central nervous system. We have identified four Phase I metabolites after oral administration. The major metabolic routes are N-demethylation, aliphatic hydroxylation and O-methylation of a demethylenate intermediate.
Discussion:
Pharmacokinetic and pharmacodynamic analysis of methylone showed a correlation between plasma concentrations and enhancement of the locomotor activity. A contribution of metabolites in the activity of methylone after oral administration is suggested. Present results will be helpful to understand the time course of the effects of this drug of abuse in humans.
Recreational use of the cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV; "bath salts") has increased worldwide in past years, accompanied by accounts of health and legal problems in the popular media and efforts to criminalize possession in numerous jurisdictions. Minimal information exists on the effects of MDPV in laboratory models. This study determined the effects of MDPV, alongside those of the better studied stimulant d-methamphetamine (METH), using rodent models of intravenous self-administration (IVSA), thermoregulation and locomotor activity. Male Wistar rats were trained to self-administer MDPV or METH (0.05 mg/kg/infusion, i.v.) or were prepared with radiotelemetry implants for the assessment of body temperature and activity responses to MDPV or METH (0-5.6 mg/kg s.c.). METH and MDPV were consistently self-administered within 10 training sessions (mg/kg/hour; METH Mean=0.4 and Max = 1.15; MDPV Mean=0.9 and Max = 5.8). Dose-substitution studies demonstrated that behavior was sensitive to dose for both drugs, but MDPV (0.01-0.50 mg/kg/inf) showed greater potency and efficacy than METH (0.1-0.25 mg/kg/inf). In addition, both MDPV and METH increased locomotor activity at lower doses (0.5-1.0 mg/kg, s.c.) and transiently decreased activity at the highest dose (5.6 mg/kg, s.c.). Body temperature increased monotonically with increasing doses of METH but MDPV had a negligible effect on temperature. Stereotypy was associated with relatively high self-administered cumulative doses of MDPV (∼1.5 mg/kg/hr) as well as with non-contingent MDPV administration wherein the intensity and duration of stereotypy increased as MDPV dose increased. Thus, MDPV poses a substantial threat for compulsive use that is potentially greater than that for METH.
The rise in popularity of "bath salts" as safe alternatives to MDMA (3,4-methylenedioxymethamphetamine), methamphetamine, and other illicit substances has resulted in increased scrutiny of the contents and toxicology associated with these products. We report a case of sudden death related to the synthetic cathinone methylone (3,4-methylenedioxy-N-methylcathinonmethylone) in a previously healthy 19-year-old man. Although several fatal case reports have been published involving methylone and other synthetic cathinones, this is the first reported case of sudden cardiac death associated with methylone use. Although lack of published data prevented a comparison of blood methylone concentrations between our case and existing reports, the amount of methylone we detected postmortem (0.07 mg/dL) is below those reported in MDMA-related fatalities. Our report suggests that methylone toxicity has been greatly underestimated by users of this synthetic cathinone.
Recreational use of the drug 4-methylmethcathinone (mephedrone; 4-MMC) became increasingly popular in the United Kingdom in recent years, spurred in part by the fact that it was not criminalized until April 2010. Although several fatalities have been associated with consumption of 4-MMC and cautions for recreational users about its addictive potential have appeared on Internet forums, very little information about abuse liability for this drug is available. This study was conducted to determine if 4-MMC serves as a reinforcer in a traditional intravenous self-administration model. Groups of male Wistar and Sprague-Dawley rats were prepared with intravenous catheters and trained to self-administer 4-MMC in 1-hour sessions. Per-infusion doses of 0.5 and 1.0 mg/kg were consistently self-administered, resulting in greater than 80% discrimination for the drug-paired lever and mean intakes of about 2-3 mg/kg/hour. Dose-substitution studies after acquisition demonstrated that the number of responses and/or the total amount of drug self-administered varied as a function of dose. In addition, radiotelemetry devices were used to show that self-administered 4-MMC was capable of increasing locomotor activity (Wistar) and decreasing body temperature (Sprague-Dawley). Pharmacokinetic studies found that the T(1/2) of 4-MMC was about 1 hour in vivo in rat plasma and 90 minutes using in vitro liver microsomal assays. This study provides evidence of stimulant-typical abuse liability for 4-MMC in the traditional pre-clinical self-administration model.
In recent years, synthetic cathinones, often labeled as "bath salts" in an attempt to evade drug laws, have emerged as substances of abuse. Sympathomimetic drugs are well known to cause rhabdomyolysis but are rarely associated with acute compartment syndrome. In this case series, we describe 3 patients who presented with sympathomimetic signs or symptoms including hyperthermia and agitation and had confirmed synthetic cathinone use. All 3 patients had severe rhabdomyolysis with delayed development of an acute compartment syndrome. Two patients developed paraspinal compartment syndromes, whereas 1 developed bilateral forearm compartment syndromes. Management included fasciotomy in 2 patients and medical management in the third. Two of the 3 patients made a complete recovery before hospital discharge; the third patient was hemodialysis dependent at 5-month follow-up.
Naphyrone (1-naphthalen-2-yl-2-pyrrolidin-1-yl-pentan-1-one; naphthylpyrovalerone, β-naphyrone) is a cathinone designer drug and was marketed as replacement for the synthetic cathinone derivative mephedrone. Meanwhile, naphyrone is also classified as a controlled drug in several countries. Therefore, the aim of this study was to identify the metabolites of naphyrone in rat urine using gas chromatography-mass spectrometry techniques and to show its detectability in urine samples. The following metabolic steps could be detected in rat urine: oxidation of the pyrrolidine ring to the corresponding lactam, hydroxylation of the propyl side chain and the naphthyl ring, degradation to the primary amines after opening of the pyrrolidine ring, and combinations of these steps. Assuming similar kinetics, an intake of naphyrone should be detectable in human urine mainly via its metabolites. Copyright © 2013 John Wiley & Sons, Ltd.
Background and purpose:
Bath salts is the street name for drug combinations that contain synthetic cathinone analogues, among them possibly mephedrone (MEPH) and certainly methylenedioxypyrovalerone (MDPV). In animal studies, cathinone and certain cathinone analogues release dopamine (DA), similar to the action of amphetamine (AMPH) and methamphetamine (METH). AMPH and METH act on the human DA transporter (hDAT); thus, we investigated MEPH and MDPV acting at hDAT.
Experimental approach:
We recorded electrical currents mediated by hDAT expressed in Xenopus laevis oocytes and exposed to: DA, METH, a known hDAT stimulant and DA releaser, MEPH, MDPV, MEPH + MDPV, or cocaine, a known hDAT inhibitor.
Key results:
DA, METH and MEPH induce an inward current (depolarizing) when the oocyte is held near the resting potential (-60 mV), therefore acting as excitatory hDAT substrates. Structurally analogous MDPV induces an outward (hyperpolarizing) current similar to cocaine, therefore acting as an inhibitory non-substrate blocker.
Conclusions and implications:
Two components of bath salts, MEPH and MDPV, produce opposite effects at hDAT that are comparable with METH and cocaine, respectively. In our assay, MEPH is nearly as potent as METH; however, MDPV is much more potent than cocaine and its effect is longer lasting. When applied in combination, MEPH exhibits faster kinetics than MDPV, viz., the MEPH depolarizing current occurs seconds before the slower MDPV hyperpolarizing current. Bath salts containing MEPH (or a similar drug) and MDPV might then be expected initially to release DA and subsequently prevent its reuptake via hDAT. Such combined action possibly underlies some of the reported effects of bath salts abuse.
The growing abuse of toxic stimulants known as "bath salts" can cause psychosis and possibly death. Raising awareness of the dangers through patient counseling and community outreach programs will be important-especially efforts aimed at young people.