methylone and mephedrone

The synthetic cathinones are a class of designer drugs of abuse that share a common core scaffold. The pharmacokinetic profiles of the synthetic cathinones vary based on the substitutions to the core scaffold.. To provide a summary of the literature regarding the pharmacokinetic characteristics of the synthetic cathinones, with a focus on the impact of the structural modifications to the pharmacokinetics.. In many, but not all, instances the pharmacokinetic characteristics of the synthetic cathinones can be reasonably predicted based on the substitutions to the core scaffold. Mephedrone and methylone are chemically alike and have similar T. Continued research will lead to a better understanding of the pharmacokinetic changes associated with structural modifications to the cathinone scaffold, and potentially in the long range, enhanced overdose and addiction therapy. Additionally, the areas of polydrug use and pharmacogenetics have been largely overlooked with regard to synthetic cathinones.

Topics: Alkaloids; Amphetamines; Animals; Designer Drugs; Humans; Methamphetamine; Substance-Related Disorders; Synthetic Drugs

Cathinone is a plant alkaloid found in khat leaves of perennial shrubs grown in East Africa. Similar to cocaine, cathinone elicits psychostimulant effects which are in part attributed to its amphetamine-like structure. Around 2010, home laboratories began altering the parent structure of cathinone to synthesize derivatives with mechanisms of action, potencies, and pharmacokinetics permitting high abuse potential and toxicity. These "synthetic cathinones" include 4-methylmethcathinone (mephedrone), 3,4-methylenedioxypyrovalerone (MDPV), and the empathogenic agent 3,4-methylenedioxymethcathinone (methylone) which collectively gained international popularity following aggressive online marketing as well as availability in various retail outlets. Case reports made clear the health risks associated with these agents and, in 2012, the Drug Enforcement Agency of the United States placed a series of synthetic cathinones on Schedule I under emergency order. Mechanistically, cathinone and synthetic derivatives work by augmenting monoamine transmission through release facilitation and/or presynaptic transport inhibition. Animal studies confirm the rewarding and reinforcing properties of synthetic cathinones by utilizing self-administration, place conditioning, and intracranial self-stimulation assays and additionally show persistent neuropathological features which demonstrate a clear need to better understand this class of drugs. This Review will thus detail (i) historical context of cathinone use and the rise of "dark" synthetic derivatives, (ii) structural features and mechanisms of synthetic cathinones, (iii) behavioral effects observed clinically and in animals under controlled laboratory conditions, and (iv) neurotransmitters and circuits that may be targeted to manage synthetic cathinone abuse in humans.

Topics: Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Body Temperature; Catha; Central Nervous System Stimulants; Dopamine; History, 21st Century; History, Medieval; Humans; Locomotion; Methamphetamine; Pyrrolidines; Serotonin; Substance-Related Disorders; Synaptic Transmission; Synthetic Cathinone

Animal models of drug self-administration are currently the gold standard for making predictions regarding the relative likelihood that a recreational drug substance will lead to continued use and addiction. Such models have been found to have high predictive accuracy and discriminative validity for a number of drug classes including ethanol, nicotine, opioids, and psychostimulants such as cocaine and methamphetamine. Members of the entactogen class of psychostimulants (drugs that produce an "open mind state" including feelings of interpersonal closeness, intimacy and empathy) have been less frequently studied in self-administration models. The prototypical entactogen 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") supports self-administration but not with the same consistency nor with the same efficacy as structurally related drugs amphetamine or methamphetamine. Consistent with these observations, MDMA use is more episodic in the majority of those who use it frequently. Nevertheless, substantial numbers of MDMA users will meet the criteria for substance dependence at some point in their use history. This review examines the currently available evidence from rodent self-administration studies of MDMA and two of the new and emerging psychoactive substances (NPS) that produce entactogen type neuropharmacological responses - mephedrone (4-methylmethcathinone; 4MMC; "meow meow") and methylone (3,4-methylenedioxymethcathinone). Overall, the current evidence predicts that these NPS entactogens have enhanced abuse liability compared with MDMA.

Topics: Animals; Behavior, Animal; Methamphetamine; Models, Animal; N-Methyl-3,4-methylenedioxyamphetamine; Psychotropic Drugs; Rats; Self Administration; Substance-Related Disorders

New psychoactive substances have drastically modified the world drug scene. An increasingly popular class comprises synthetic or substituted cathinones (legal highs, research chemicals, bath salts). Among the most common psychoactive constituents of bath salts are mephedrone and methylone. Recent reports on the abuse of novel synthetic cathinone derivatives call attention to the serious physical and psychological risks resulting from their consumption, thereby emphasizing the growing use of these drugs might constitute an important public health issue. In this paper, we will review the available data regarding the use and effects of mephedrone and methylone in humans in order to highlight their impact on public health. To reach this objective, a literature search was performed on two representative databases (Pubmed, Google Scholar), the Erowid Center website (a US non-profit educational organization that provides information about psychoactive plants and chemicals), and various governmental websites. The terms used for the database search were "mephedrone", "methylone", "new psychoactive substances", "synthetic cathinones", "substituted cathinones", "substance abuse", "substance use disorder", "adverse effects", "fatalities". The literature search was limited to years 2005-2015 and led to the identification of 71 potentially relevant articles. To date, the actual prevalence rates of their use remains difficult to estimate. Important health-related issues have emerged in relation to the somatic, psychiatric, and addictive consequences of their use. The potential chronic health effects of their prolonged use remain to date unknown (e.g., reproductive toxicity, genotoxicity and carcinogenic potential). Treatment for patients with prolonged exposure to synthetic cathinones should ideally include a drug management plan coupled with psychotherapy taking place in a structured program of care.

Topics: Animals; Central Nervous System Stimulants; Databases, Bibliographic; Humans; Methamphetamine; Substance-Related Disorders

"Bath salts" is one street name for a family of synthetic cathinones that display pharmacological effects resembling cocaine and commonly abused amphetamines. Despite extensive legislation aimed at the criminalization of bath salts, several designer cathinones are gaining a foothold in the illicit drug scene; for example, in the United Kingdom, mephedrone (4-methylmethcathinone, MEPH) is highly popular among drug abusers whereas, in the United States, MDPV (methylenedioxypyrovalerone) and methylone are highly prevalent. To date, knowledge about the hazards of designer cathinones is based mostly on hospital reports and anecdotal evidence derived from online surveys. Despite the paucity of preclinical studies directed toward designer cathinones, a number of invaluable findings arising from those studies are enabling scientists to develop their neuropharmacological profiles. Despite their commonalities in chemical structures, synthetic cathinones possess distinct neuropharmacological profiles and produce different behavioral effects, including unique effects on locomotor activity, learning, anxiety, thermoregulation, and abuse liability. The present review will discuss the behavioral effects of MEPH, MDPV, and methylone and compare those effects to established psychostimulant drugs. The rise in the use of designer cathinones in the United States and abroad justifies further investigations into these compounds, both for a greater understanding of the danger that "bath salts" pose to the public, and to provide insight into replacement cathinones as they emerge onto the market.

Topics: Alkaloids; Animals; Benzodioxoles; Central Nervous System Stimulants; Designer Drugs; Drug Evaluation, Preclinical; Humans; Illicit Drugs; Methamphetamine; Pyrrolidines; Substance-Related Disorders; Synthetic Cathinone

Designer drugs belong to a group of legally or illegally produced substances that are structurally and pharmacologically very similar to illicit drugs. In the past, designer drugs were often used during all-night dance parties, but they are now consumed in multiple settings from college bars to parks to private house parties. Most of these club drugs can be bought on legal websites and home-delivered for private parties. Recently, legal highs have once again become a burning media issue across the world. Our review will focus on GHB and synthetic cathinones. Literature searches were conducted for the period from 1975 to July 2010 using PubMed, EMBASE, PsycInfo, Internet underground and governmental websites using the following keywords alone or in combination: designer drugs, club drugs, party drugs, GHB, synthetic cathinones, mephedrone, methylone, flephedrone, MDAI, and MDVP. Available epidemiological, neurobiological, and clinical data for each compound are described. There is evidence that negative health and social consequences may occur in recreational and chronic users. The addictive potential of designer drugs is not weak. Non-fatal overdoses and deaths related to GHB/GBL or synthetic cathinones have been reported. Clinicians must be careful with GBL or synthetic cathinones, which are being sold and used as substitutes for GHB and MDMA, respectively. Interventions for drug prevention and harm reduction in response to the use of these drugs should be implemented on the Internet and in recreational settings. Prevention, Information, Action, and Treatment are the main goals that must be addressed for this new potentially addictive problem.

Topics: Alkaloids; Animals; Designer Drugs; Humans; Illicit Drugs; Indans; Methamphetamine; N-Methyl-3,4-methylenedioxyamphetamine; Sodium Oxybate; Substance-Related Disorders

Synthetic cathinones display overlapping behavioral effects with psychostimulants (e.g., methamphetamine [MA]) and/or entactogens (e.g., 3,4-methylenedioxymethaphetamine [MDMA])-presumably reflecting their dopaminergic and/or serotonergic activity. The discriminative stimulus effects of MDMA thought to be mediated by such activity have been well characterized in rodents but have not been fully examined in nonhuman primates.. The present studies were conducted to systematically evaluate the discriminative stimulus effects of 5 abused synthetic cathinones (methylenedioxypyrovalerone [MDPV], α-pyrrolidinovalerophenone [α-PVP], methcathinone [MCAT], mephedrone, and methylone) in adult male squirrel monkeys trained to distinguish intramuscular injections of MA (0.1 mg/kg; n = 4) or MDMA (0.6 mg/kg; n = 4) from vehicle.. Each training drug produced dose-dependent effects and, at the highest dose, full substitution. MDMA produced predominantly vehicle-like responding in the MA-trained group, whereas the highest dose of MA (0.56 mg/kg) produced partial substitution (approximately 90% appropriate lever responding in one-half of the subjects) in the MDMA-trained group. MDPV, α-PVP, and MCAT produced full substitution in MA-trained subjects, but, at the same or higher doses, only substituted for MDMA in one-half of the subjects, consistent with primarily dopaminergically mediated interoceptive effects. In contrast, mephedrone and methylone fully substituted in MDMA-trained subjects but failed to fully substitute for the training drug in MA-trained subjects, suggesting a primary role for serotonergic actions in their interoceptive effects.. These findings suggest that differences in the interoceptive effects of synthetic cathinones in nonhuman primates reflect differing compositions of monoaminergic actions that also may mediate their subjective effects in humans.

Topics: Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Central Nervous System Stimulants; Discrimination Learning; Interoception; Male; Methamphetamine; N-Methyl-3,4-methylenedioxyamphetamine; Propiophenones; Psychotropic Drugs; Pyrrolidines; Saimiri; Synthetic Cathinone

Approximately 10 years ago, "bath salts" became popular as legal alternatives to the psychostimulants cocaine and the amphetamines. These products contained synthetic cathinones, including 3,4-methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4-methylenedioxymethcathinone (methylone). Most preclinical investigations have only assessed the effects of these synthetic cathinones independently; however, case reports and Drug Enforcement Administration (DEA) studies indicate that bath salts contain mixtures of these substances. In this study, we examine the pharmacokinetic interactions of the drug combination. We hypothesized that combined exposure to MDPV, mephedrone, and methylone would result in increased drug concentrations and enhanced total drug concentrations when compared to individual administration.. Adolescent male Swiss-Webster mice were injected intraperitoneally with either 10 mg/kg MDPV, 10 mg/kg mephedrone, 10 mg/kg methylone, or 10 mg/kg combined MDPV, mephedrone, and methylone. Following injection, brains and plasma were collected at 1, 10, 15, 30, 60, and 120 min. Drugs were extracted via solid-phase extraction, and concentrations were determined using a previously published high-pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method.. All drugs crossed the blood-brain barrier quickly. For methylone, the maximal concentration (C. The pharmacokinetics of methylone, mepedrone, and MDPV are altered when the drugs are used in combination. These data provide insight into the consequences of co-exposure to synthetic cathinones in popular bath salt products.

Topics: Alkaloids; Animals; Benzodioxoles; Blood-Testis Barrier; Brain; Central Nervous System Stimulants; Chromatography, High Pressure Liquid; Male; Methamphetamine; Mice; Pyrrolidines; Salts; Synthetic Cathinone; Tandem Mass Spectrometry

Synthetic cathinones share potent sympathomimetic properties with amphetamines due to their shared phenethylamine backbone. Despite recent work focused on understanding the behavioral effects of synthetic cathinones, a systematic comparison of neuropharmacology, behavior, and physiological effects with other stimulants, has remained elusive. In the present study, we explore the behavioral effects of cathinones in crayfish, a model system which combines a well characterized behavioral paradigm for addiction-like behaviors, a modularly organized nervous system, the lack of a formal blood-brain barrier, and experimental tractability. The objective of this study was to characterize the psychomotor and rewarding effects of methylated cathinones (methylone, mephedrone), and their non β-ketone substituted amphetamine analogs (4-methylmethamphetamine, 4-MMA and 3,4-methylenedioxymethamphetamine MDMA) in crayfish. Our results suggest that these drugs produce psychostimulation, which sensitizes upon repeated drug administration. Furthermore, crayfish demonstrated a conditioned substrate preference for mephedrone and 4-MMA drug-pairings at a 10 μg/g dose, a preference which persisted even through a series of extinction trials. Our study indicates that synthetic cathinones and substituted amphetamine analogues produce distinct behavioral effects in an invertebrate system which consists of a relatively simple neuronal organization. The present findings provide an evolutionary context to our understanding about how drugs of abuse initiate reward at levels far beyond those specific to humans.

Topics: Alkaloids; Amphetamines; Animals; Astacoidea; Behavior, Animal; Central Nervous System Sensitization; Central Nervous System Stimulants; Conditioning, Psychological; Male; Methamphetamine; Motor Activity; N-Methyl-3,4-methylenedioxyamphetamine; Phenethylamines; Reward

The constant legal adaptation of new psychoactive substances (NPS), challenges their evaluation in different fields. In sports, NPS are prohibited in competition with a reporting limit (RL) of 50 ng/mL for the parent compound or a metabolite. However, there is a lack of comprehensive methodologies and excretion studies for monitoring NPS. This work aims to develop an analytical methodology for the NPS quantification and to evaluate the suitability of monitoring the urinary parent stimulants after NPS misuse. A method for the quantification of 14 common NPS was developed and validated. The method was found to be linear in the range 1-1000 ng/mL, and was shown to be accurate and precise. A lowest limit of quantification (LLOQ) of 1 ng/mL was established for all analytes except for benzylpiperazine (5 ng/mL). The method was able to confirm the identity of the analytes at the LLOQ for most NPS. The methodology was applied to the quantification of the parent compound in urine samples collected from an observational study where several healthy volunteers (n ≥ 6 per drug) ingested active doses of mephedrone (MEPH), methylone (MDMC), 2,5-dimetoxy-4-ethylphenetylamine (2C-E), or 6-(2-aminopropyl)benzofuran (6-APB). It was observed that for MDMC and 6-APB, the quantification of the urinary parent drug at the current RL is a proper strategy for detecting their misuse. However, this strategy seems to be insufficient for evaluating MEPH and 2C-E misuse. Monitoring the most abundant metabolite of MEPH (4'-carboxy-MEPH) and the reduction of the RL to 10 ng/mL for the 2C-E evaluation are proposed.

Topics: Adult; Central Nervous System Stimulants; Chromatography, High Pressure Liquid; Doping in Sports; Female; Humans; Illicit Drugs; Limit of Detection; Male; Mass Spectrometry; Methamphetamine; Prospective Studies; Psychotropic Drugs; Reference Standards; Reproducibility of Results; Substance Abuse Detection

New psychoactive substances (NPS) are still an emerging issue in clinical and forensic toxicology. Information about their cytotoxic potential is limited or even unavailable before distribution and thus their intake can be of high risk for consumers. The aim of the presented study was to develop a strategy to identify cytotoxic potential of NPS based on a high content screening assay (HCSA) using HepG2 cell line and four fluorescent dyes, namely Hoechst33342, TMRM, CAL-520, and TOTO-3. The HCSA was optimized to work without an automated analyzer by using the model compounds fluvastatin, paracetamol, propranolol, and simvastatin. The following parameters were monitored: stained nuclei as a measure for cell count as well as nuclear size and nuclear intensity (all Hoechst33342), mitochondrial membrane potential (TMRM), cytosolic calcium level (CAL-520), and plasma membrane integrity (TOTO-3). The present study showed strong cytotoxic potential for the NPS 5F-PB-22 and MDAI, moderate effects for MDMA, MDPV, methylone, cathinone, 4-MEC, and mephedrone, and no toxic effects for methamphetamine. To assess the metabolic suitability of HepG2 cells under the chosen conditions, cell culture supernatants were analyzed by liquid chromatography-high resolution-tandem mass spectrometry. Metabolites were merely detected for lipophilic drugs such as 5F-PB-22 and MDPV and in addition with a much lower abundance in comparison to the parent compound but the study only allowed a qualitative look for metabolites and the used liver cell line might not ideal when considering metabolism.

Topics: Acetaminophen; Alkaloids; Biological Assay; Chromatography, Liquid; Fluorescent Dyes; Fluvastatin; Hep G2 Cells; Hepatocytes; Humans; Illicit Drugs; Indans; Indoles; Membrane Potential, Mitochondrial; Methamphetamine; N-Methyl-3,4-methylenedioxyamphetamine; Propranolol; Quinolines; Simvastatin; Tandem Mass Spectrometry; Toxicity Tests

Designer drug mixtures popularized as "bath salts" often contain the synthetic cathinones 3,4 methylenedioxypyrovalerone (MDPV), mephedrone, and methylone in various combinations. However, most preclinical investigations have only assessed the effects of individual bath salt constituents, and little is known about whether co-exposure to MDPV, mephedrone, and methylone produces significant neuropharmacological interactions. This study evaluated and compared how MDPV, mephedrone, and methylone influence discrete brain tissue dopamine (DA) levels and motor stimulant responses in mice when administered alone and as a ternary mixture. Male adolescent Swiss-Webster mice received intraperitoneal injections of saline or 1 or 10 mg/kg doses of MDPV, mephedrone, or methylone, or a cocktail of all three cathinones at doses of 1, 3.3, or 10 mg/kg each. The effect of each treatment on DA and DA metabolite levels in mesolimbic and nigrostriatal brain tissue was quantified 15 min after a single exposure using HPLC-ECD. Additionally, locomotor activity was recorded in mice after acute (day 1) and chronic intermittent (day 7) dosing. MDPV, mephedrone, and methylone produced dose-related increases in mesolimbic and nigrostriatal DA levels that were significantly enhanced following their co-administration. In addition, mice treated with the cathinone cocktail displayed decreased locomotor activity on day 1 that was exacerbated by day 7 and not observed with any of the drugs alone. Our findings demonstrate a significant enhanced effect of MDPV, mephedrone, and methylone on both DA, and these effects on DA result in significant alterations in locomotor activity.

Topics: Animals; Benzodioxoles; Brain; Corpus Striatum; Designer Drugs; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Limbic Lobe; Locomotion; Male; Methamphetamine; Mice; Pyrrolidines; Substantia Nigra; Synthetic Cathinone

Synthetic cathinones are popular psychoactive substances that may cause skeletal muscle damage. In addition to indirect sympathomimetic myotoxicity, these substances could be directly myotoxic. Since studies in myocytes are currently lacking, the aim of the present study was to investigate potential toxicological effects by synthetic cathinones on C2C12 myoblasts (mouse skeletal muscle cell line). We exposed C2C12 myoblasts to 3-methylmethcathinone, 4-methylmethcathinone (mephedrone), 3,4-methylenedioxymethcathinone (methylone), 3,4-methylenedioxypyrovalerone (MDPV), alpha-pyrrolidinovalerophenone (α-PVP), and naphthylpyrovalerone (naphyrone) for 1 or 24 h before cell membrane integrity, ATP content, mitochondrial oxygen consumption, and mitochondrial superoxide production was measured. 3,4-Methylenedioxymethamphetamine (MDMA) was included as a reference compound. All investigated synthetic cathinones, as well as MDMA, impaired cell membrane integrity, depleted ATP levels, and increased mitochondrial superoxide concentrations in a concentration-dependent manner in the range of 50⁻2000 μM. The two pyrovalerone derivatives α-PVP and naphyrone, and MDMA, additionally impaired basal and maximal cellular respiration, suggesting mitochondrial dysfunction. Alpha-PVP inhibited complex I, naphyrone complex II, and MDMA complex I and III, whereas complex IV was not affected. We conclude that, in addition to sympathetic nervous system effects and strenuous muscle exercise, direct effects of some cathinones on skeletal muscle mitochondria may contribute to myotoxicity in susceptible synthetic cathinone drugs users.

Topics: Adenosine Triphosphate; Animals; Benzodioxoles; Cell Line; Methamphetamine; Mice; Mitochondria; Myoblasts; Oxygen Consumption; Pentanones; Psychotropic Drugs; Pyrrolidines; Superoxides; Synthetic Cathinone

"Bath salts" preparations contain synthetic cathinones which interact with monoamine transporters and function as either monoamine uptake inhibitors or releasers. 3,4-Methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), and 4-methylmethcathinone (mephedrone) were three of the most common cathinones (i.e., "first-generation" cathinones); however, after the US Drug Enforcement Administration placed them under Schedule I regulations, they were replaced with structurally related cathinones that were not subject to regulations (i.e., "second-generation" cathinones). Although the reinforcing effects of some second-generation cathinones have been described (e.g., α-pyrrolidinopentiophenone [α-PVP]), little is known about how structural modifications, particularly those involving the methylenedioxy moiety and α-alkyl side chain, impact the abuse liability of other second-generation cathinones (e.g., α-pyrrolidinopropiophenone [α-PPP], 3,4-methylenedioxy-α-pyrrolidinobutiophenone [MDPBP], and 3,4-methylenedioxy-α-pyrrolidinopropiophenone [MDPPP]). The present study used male Sprague-Dawley rats (n = 12 per drug) to directly compare: (1) the acquisition of responding for α-PVP (0.032 mg/kg/inf), α-PPP (0.32 mg/kg/inf), MDPBP (0.1 mg/kg/inf), and MDPPP (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement; and (2) full dose-response curves for each drug to maintain responding under an FR5 schedule of reinforcement. The average number of days (∼4 days) and percentage (100%) of rats that acquired self-administration was similar for each drug. The observed rank order potency to maintain responding under an FR5 schedule of reinforcement (α-PVP ≈ MDPBP>α-PPP > MDPPP) is consistent with their potencies to inhibit dopamine uptake. These are the first studies to report on the reinforcing effects of the unregulated second-generation cathinones MDPBP, MDPPP, and α-PPP and indicate all three compounds are readily self-administered, suggesting each possesses high potential for abuse. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

Topics: Analysis of Variance; Animals; Benzodioxoles; Conditioning, Operant; Designer Drugs; Dose-Response Relationship, Drug; Inhibitory Concentration 50; Male; Methamphetamine; Pyrrolidines; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Reinforcement, Psychology; Self Administration; Synthetic Cathinone

Wastewater-based epidemiology (WBE) is considered to be a useful tool for monitoring chemical consumption in the population. However, the lack of information on potential transformation of biomarkers in the sewer system can compromise the accuracy of the consumption estimation. The present study contributes to addressing this issue by investigating the in-sewer stability of biomarkers from a number of commonly used drugs using laboratory sewer reactors that can mimic different sewer conditions. A stable and an unstable chemical (carbamazepine and caffeine) were also used as benchmarking chemicals to reflect the chemical degradation potential in different sewer conditions. The results suggested that ketamine and norketamine were unstable in gravity and rising main sewers, ketamine was unstable in bulk liquid while norketamine was stable under the same condition. Similarly, mephedrone and methylone were unstable in sewer conditions with considerable deviation. Significant loss of buprenorphine, methadone, oxycodone and codeine was observed in the rising main sewer. Morphine and codeine glucuronide were found to be deconjugated from their glucuronides quickly in the presence of biofilms. This study indicates that it is important to evaluate the stability of biomarkers in the sewer system before using them in WBE for estimating consumption/exposure to reduce uncertainties.

Topics: Biofilms; Biomarkers; Carbamazepine; Codeine; Environmental Monitoring; Illicit Drugs; Ketamine; Methamphetamine; Sewage; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical

In recent years, the abuse of synthetic cathinones or 'bath salts' has become a major public health concern. Although these compounds were initially sold legally and labeled "not for human consumption", the 'bath salts' are psychostimulants, with similar structures and pharmacologic mechanisms to cocaine, the amphetamines, and 3,4 methylendioxymethamphetamine (MDMA, Molly, or Ecstasy). The reported use of these substances by women of child-bearing age highlights the necessity of studies seeking to delineate risks of prenatal exposure. Three popular drugs of this type are methylone, mephedrone, and 3, 4-methylenedioxypyrovalerone (MDPV). Unfortunately, there is currently no information available on the teratogenicity of these compounds, or of the extent to which they cross the placenta. As such, the purpose of this study was to examine the pharmacokinetic profile of the 'bath salts' in a pregnancy model. Pregnant mice (E17.5 gestation) were injected intraperitoneally with a cocktail of 5mg/kg methylone, 10mg/kg mephedrone, and 3mg/kg (MDPV) dissolved in sterile saline. Maternal brain, maternal plasma, placenta, and fetal brain were collected at 30s, 1min, 5min, 10min, 15min, 30min, 1h, 2h, 4h, and 8h following injection. Methylone, mephedrone, and MDPV were extracted from tissue by solid phase extraction, and concentrations were determined using a previously validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Interestingly, all 3 cathinones reached measurable concentrations in the placenta, as well as the fetal brain; in fact, for MDPV, the maximal concentration (Cmax) was highest in fetal brain, while mephedrone's highest Cmax value was achieved in placenta. Additionally, the total drug exposure for all 3 compounds (as represented by area under the curve, AUC) was higher in fetal matrices (placenta and fetal brain) than in maternal matrices (maternal brain and plasma), and the half-lives for the drugs were longer. Given the extensive presence of methylone, mephedrone, and MDPV in the fetal brain following prenatal exposure, fetal risk is definitely a concern. As there are currently no prenatal studies available on the teratogenicity of these agents, pregnant patients should be informed about the potential risks that these substances may have.

Topics: Alkaloids; Animals; Brain; Central Nervous System Stimulants; Female; Methamphetamine; Mice; Pregnancy; Pyrrolidines

Workplace drug testing in Australia is usually adherent to one of two standards, AS/NZS 4308:2008 for urine or AS 4760:2006 for oral fluid. These standards prescribe the drugs tested, devices used and testing methodology followed by the testing agency. However, they are not comprehensive and for many years workers have been able to consume novel psychoactive substances to avoid detection and without consequences. Here, we present a validated method for the detection of 32 Synthetic Stimulant and Hallucogenic drugs, commonly sold as bath salts, in oral fluid. These drugs are cathinone, ephedrone, methylone, flephedrone, MDA, PMA, methedrone, TMA, MDMA, butylone, mephedrone, MDEA, MEC, pentedrone, MBDB, MTA, Alpha-PVP, MPBP, 2C-B, MDPV, DOB, 2C-T-2, TFMPP, DOET, 2C-T-7, naphyrone, MDAI, FMA, DMA, 25C-NBOMe, 25B-NBOMe and 25T4-NBOMe. Sample preparation was undertaken using a simple protein precipitation in acetonitrile. Chromatographic separation was achieved in 7.5 min on a Kinetex F5 column (50 mm × 3 mm × 2.6 μm) using 0.1% formic acid in water and acetonitrile as the mobile phases. The method was validated with limit of detection (1 ng/mL), limit of quantitation (2.5 ng/mL), selectivity, linearity (2.5-500 ng/mL), accuracy (85.3-108.4% of the target concentration) and precision (1.9-14%). This method was applied to 12 samples previously submitted for routine testing and two were found to contain 2-CB and DOB (5 and 4 ng/mL) and, MPBP and TFMPP (both at 4 ng/mL). This method provides for the rapid detection of a large number of compounds in oral fluid which is readily applicable to routine testing laboratories.

Topics: Alkaloids; Anisoles; Australia; Benzylamines; Dimethoxyphenylethylamine; Humans; Illicit Drugs; Methamphetamine; Pentanones; Phenethylamines; Propiophenones; Psychotropic Drugs; Pyrrolidines; Saliva; Substance Abuse Detection

Synthetic cathinones have become popular in recent years, which would explain why their determination in influent sewage samples has already been documented. In the present study a method based on solid-phase extraction followed by liquid chromatography and high resolution mass spectrometry is developed, validated and applied to determine twelve cathinones and one of their metabolites in different environmental samples including influent and effluent sewage and river water. Two cation-exchange sorbents (Oasis MCX and Oasis WCX) were compared, with better results achieved with Oasis WCX in terms of apparent recoveries (70-100%) and matrix effects (lower than -34%). The method was validated with effluent sewage samples providing suitable figures of merit, with method quantification limits ranging from 1ng/L to 5ng/L and method detection limits from 0.1ng/L to 0.5ng/L for all the compounds. Of the different cathinones studied, three, namely methylone, mephedrone metabolite and methylenedioxypyrovalerone, were quantified at concentration levels of low ng/L in each of the different samples analysed, while a number of the other cathinones were also detected in some of the samples.

Topics: Alkaloids; Chromatography, Liquid; Environmental Monitoring; Fresh Water; Limit of Detection; Methamphetamine; Sewage; Solid Phase Extraction; Tandem Mass Spectrometry; Water Pollutants, Chemical

The recreational use of substituted cathinones continues to grow as a public health concern in the United States. Studies have shown that extended access to intravenous (i.v.) self-administration of stimulants, such as cocaine and methamphetamine, results in escalation of drug intake relative to shorter access; however, little is known about the impact of extended access on self-administration of entactogen class stimulants such as methylone and 4-methylmethcathinone (mephedrone). Male Wistar rats were randomly assigned to short-access (ShA, 2- h) and long-access (LgA, 6- h) groups and trained to self-administer methylone or mephedrone (0.5 mg/kg/infusion) using a fixed-ratio 1 response contingency. The methylone-trained groups were evaluated on a progressive-ratio (PR) procedure incorporating dose-substitution of methylone (0.125-2.5 mg/kg/infusion), mephedrone (0.125-2.5 mg/kg/infusion) or methamphetamine (MA; 0.01-0.5 mg/kg/infusion). Mephedrone-trained rats were similarly evaluated on a PR with mephedrone and MA. Rats trained with LgA to methylone and mephedrone earned more infusions during acquisition compared with ShA groups. Mephedrone-trained LgA rats reached significantly higher breakpoints than all other groups in mephedrone and MA PR tests. Methylone-trained LgA rats exhibited a rightward shift of the peak effective dose but no overall efficacy change compared with methylone-trained ShA rats. These findings show that the self-administration of mephedrone escalates under LgA conditions in a manner similar to traditional stimulants whereas escalation of 6 h intakes of methylone is not accompanied by differences in PR performance. Thus mephedrone represents the greater risk for dysregulated drug consumption.

Topics: Administration, Intravenous; Animals; Behavior, Animal; Central Nervous System Stimulants; Conditioning, Operant; Male; Methamphetamine; Rats; Rats, Wistar; Self Administration; Time Factors

Synthetic cathinones are beta-ketone amphetamine analogs that have emerged as a heterogeneous class of abused compounds that function as either monoamine transporter substrates or inhibitors. Pre-clinical drug discrimination procedures are useful for interrogating structure-activity relationships of abuse-related drug effects; however, in vivo structure-activity relationship comparisons between synthetic cathinones with different mechanisms of action are lacking. The aim of the present study was to determine whether the cocaine-like discriminative stimulus effects of the monoamine transporter inhibitor alpha-pyrrolidinovalerophenone (alpha-PVP) and the monoamine transporter substrate methcathinone were differentially sensitive to 3,4-methylenedioxy and 4-methyl substitutions. Male rhesus monkeys (n = 4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Potency and timecourse of cocaine-like discriminative stimulus effects were determined for (±)-alpha-PVP, (±)-methcathinone and their 3,4-methylenedioxy or 4-methyl analogs. Alpha-PVP and methcathinone produced dose- and time-dependent cocaine-like effects. A 3,4-methylenedioxy addition to either alpha-PVP or methcathinone (methylone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. A 4-methyl addition to alpha-PVP (pyrovalerone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. In contrast, addition of a 4-methyl moiety to methcathinone (4MMC; mephedrone) significantly attenuated efficacy to produce cocaine-like effects. Overall, these results suggest different structural requirements for cocaine-like discriminative stimulus effects of monoamine transporter inhibitor and substrate synthetic cathinone analogs. Given that 4MMC is more hydrophobic than MDMC, these results suggest that hydrophobicity may be an important determinant for limiting monoamine transporter substrate abuse-related behavioral effects.

Topics: Animals; Central Nervous System Stimulants; Cocaine; Conditioning, Operant; Discrimination Learning; Dopamine Uptake Inhibitors; Injections, Intramuscular; Macaca mulatta; Male; Methamphetamine; Propiophenones; Pyrrolidines; Reinforcement, Psychology

The study presents the characteristics of the use of new psychoactive substances (NPS), the perceived problems experienced by users, and the reasons for cessation or cutting down. The research focused mainly on synthetic cathinones and the use of 3-MMC in Slovenia.. In order to research the characteristics of NPS use, we used a questionnaire which had been developed to determine the characteristics of the use of ATS and cocaine in the context of nightlife and was elaborated in our study on the use of mephedrone. The final non-representative sample included 249 users of NPS from Slovenia, who had completed an on-line survey over a period of 5 months in 2014. Part of the sampling was conducted on the ground and with the help of peer-groups. DrogArt's outreach workers and correspondents visited open public places, clubs, and discotheques to encourage users to participate in the survey.. Most users of NPS in Slovenia have tried NPS from the groups of synthetic cathinones and amphetamines. Most respondents included in the sample (67.9%) have tried 3-MMC, while 43.0% have tried methylone and 37.3% have tried mephedrone (4-MMC). Users attributed greater risks to the use of new drugs and preferred the effects of traditional drugs to those of new drugs. The most frequently reported problems were depression (55.2% of users), concentration difficulties (44.0%), damage to the mucous membrane of the nose and to the throat (39.8%), feelings of fear and anxiety (39.4%), and tingling in the arms or legs (34.4%). The main reasons for cutting down or discontinuing the use of NPS were 'fear of the health consequences', 'actual health consequences', and 'growing weary of using'. Among users of NPS, 7% have sought help, while 9.1% have considered doing so. The results also highlight differences between the NPS drug markets in Slovenia and the United Kingdom.. In 2014, the most frequently used NPS in Slovenia were synthetic cathinones such as 3-MMC. Users experienced various problems related to the use of NPS. However, they are familiar with recommendations on harm reduction and want additional information on the harmful effects of the use of NPS. Based on the obtained results, we can develop specific interventions in the area of harm reduction.

Topics: Adolescent; Adult; Alkaloids; Amphetamine-Related Disorders; Female; Humans; Illicit Drugs; Male; Methamphetamine; Psychotropic Drugs; Slovenia; Surveys and Questionnaires; Young Adult

The abuse of synthetic cathinones, formerly marketed as "bath salts", has emerged over the last decade. Three common drugs in this class include 3,4-methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4-methylenedioxymethcathinone (methylone). An LC-MS/MS method has been developed and validated for the simultaneous quantification of MDPV, mephedrone, and methylone in brain tissue. Briefly, MDPV, mephedrone, methylone, and their deuterium-labeled analogs were subjected to solid phase extraction (SPE) and separated using an HILIC Silica Column. The HPLC was coupled to a Shimadzu IT-TOF (ion trap-time of flight) system with the electrospray source running in positive mode (+ESI). The method was validated for precision, accuracy, and extraction efficiency. All inter-day and intra-day % RSD (percent relative standard deviation) and % error values were less than 15% and extraction efficiency exceeded 80%. These conditions allowed for limits of detection of 1ng/mL for MDPV, and 5 ng/mL for both mephedrone and methylone. The limits of quantification were determined to be 5ng/mL for MDPV and 10 ng/mL for mephedrone and methylone. The method was utilized to evaluate the pharmacokinetics of these drugs in adult male rats following administration of a drug cocktail including MDPV, mephedrone, and methylone. All three compounds reached peak concentrations in the brain within 15 min. Although methylone and mephedrone were administered at the same dose, the peak concentration (C

Topics: Alkaloids; Animals; Area Under Curve; Benzodioxoles; Brain; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Half-Life; Male; Methamphetamine; Pyrrolidines; Rats; Solid Phase Extraction; Spectrometry, Mass, Electrospray Ionization; Substance-Related Disorders; Synthetic Cathinone; Tandem Mass Spectrometry

Topics: Adrenergic beta-Antagonists; Animals; Body Temperature; Carbazoles; Carvedilol; Central Nervous System Stimulants; Designer Drugs; Fever; Male; Methamphetamine; Propanolamines; Rats; Rats, Sprague-Dawley

Male rats will intravenously self-administer (IVSA) the substituted cathinone stimulants ("bath salts") mephedrone (4-methylmethcathione) and methylone (3,4-methylenedioxymethcathinone) robustly, whereas the IVSA of 3,4-methylenedioxymethamphetamine (MDMA) is inconsistent in many rat models. There are no data available on the self-administration of these drugs in female rats, thus a study was undertaken to contrast them directly. Groups of female Wistar rats were trained to self-administer mephedrone, methylone or MDMA (0.5 mg/kg/inf) under a Fixed-Ratio (FR) 1 schedule of reinforcement for 14 sessions. Following the acquisition interval, animals were evaluated in FR (0.0, 0.125, 0.25, 0.5, 1.0, 2.5 mg/kg/inf) and PR (0.125, 1.0 mg/kg/inf) dose-substitution procedures. The results show that female rats acquired the self-administration of all three compounds with intakes in mephedrone-trained rats that were significantly higher than that of methylone-trained or MDMA-trained rats. In dose-substitution under either FR or PR contingencies, however, the potencies of all three drugs were similar within the original training groups. The mephedrone-trained animals exhibited higher intakes of all drugs during dose-substitution, indicating lasting consequences of the training drug. Abuse liability of these three compounds is therefore predicted to be similar in established stimulant users but may differ in liability if they are primary drugs of initiation.

Topics: Administration, Intravenous; Animals; Central Nervous System Stimulants; Conditioning, Operant; Discrimination, Psychological; Dose-Response Relationship, Drug; Female; Hallucinogens; Methamphetamine; N-Methyl-3,4-methylenedioxyamphetamine; Rats; Rats, Wistar; Reinforcement Schedule; Self Administration; Time Factors

The intravenous self-administration (IVSA) of 3,4-methylenedioxymethamphetamine (MDMA) is inconsistent in rats, with up to half of subjects failing to acquire reliable drug intake. It is unknown if this changes under long-access conditions (6 h sessions) under which the IVSA of cocaine and methamphetamine escalates. The entactogen class cathinone stimulants which exhibit MDMA-like monoamine effects in the nucleus accumbens, mephedrone (4-methylmethcathinone) and methylone (3,4-methylenedioxymethcathinone), may support more reliable IVSA but results have been mixed. This study was designed to directly compare the IVSA of these three compounds. Groups of male Wistar rats were trained to self-administer mephedrone, methylone or MDMA (0.5 mg/kg/inf) under a Fixed-Ratio (FR) 1 schedule of reinforcement for 14 sessions. Following the acquisition interval, animals were evaluated in FR (0.0, 0.125, 0.25, 0.5, 1.0, 2.5 mg/kg/inf) and Progressive Ratio (PR; 0.125, 1.0 mg/kg/inf) dose-substitution procedures. Long access conditions escalated MDMA intake over the 6 h session but not in the first 2 h. In short access, drug intake was significantly higher in mephedrone-trained rats compared with either the methylone-trained or MDMA-trained groups during acquisition. Mephedrone resulted in the highest intakes during FR and PR dose-substitution in MDMA- and mephedrone-trained groups. Overall it was found that mephedrone is a more effective reinforcer than methylone or MDMA and represents a higher risk for compulsive use.

Topics: Administration, Intravenous; Amphetamine-Related Disorders; Animals; Catheters, Indwelling; Central Nervous System Stimulants; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Male; Methamphetamine; N-Methyl-3,4-methylenedioxyamphetamine; Rats, Wistar; Self Administration; Sex Characteristics

Abuse of synthetic cathinones, popularized as "bath salts," has increased dramatically in the USA since their debut in 2010. Preclinical behavioral studies may clarify determinants of the abuse-related effects produced by these compounds.. This study examined behavioral effects of (±)-methcathinone, (±)-3,4-methylenedioxypyrovalerone (MDPV), (±)-3,4-methylenedioxymethcathinone (methylone), and (±)-4-methylmethcathinone (mephedrone) in rats using intracranial self-stimulation (ICSS).. Male Sprague-Dawley rats (n = 18) with electrodes targeting the medial forebrain bundle responded for multiple frequencies of brain stimulation and were tested in two phases. First, dose-effect curves for methcathinone (0.1-1.0 mg/kg), MDPV (0.32-3.2 mg/kg), methylone (1.0-10 mg/kg), and mephedrone (1.0-10 mg/kg) were determined. Second, time courses were determined for effects produced by the highest dose of each compound.. Methcathinone produced dose- and time-dependent facilitation of ICSS. MDPV, methylone, and mephedrone produced dose- and time-dependent increases in low rates of ICSS maintained by low brain stimulation frequencies, but also produced abuse-limiting depression of high ICSS rates maintained by high brain stimulation frequencies. Efficacies to facilitate ICSS were methcathinone ≥ MDPV ≥ methylone > mephedrone. Methcathinone was the most potent compound, and MDPV was the longest acting compound.. All compounds facilitated ICSS at some doses and pretreatment times, which is consistent with abuse liability for each of these compounds. However, efficacies of compounds to facilitate ICSS varied, with methcathinone displaying the highest efficacy and mephedrone displaying the lowest efficacy to facilitate ICSS.

Topics: Animals; Benzodioxoles; Brain; Conditioning, Operant; Data Interpretation, Statistical; Designer Drugs; Dose-Response Relationship, Drug; Electric Stimulation; Injections; Male; Methamphetamine; Propiophenones; Pyrrolidines; Rats; Rats, Sprague-Dawley; Self Administration; Self Stimulation; Substance-Related Disorders; Synthetic Cathinone

During the last decade, there has been a worldwide increase in popularity and abuse of synthetic cathinones. Common ingredients of the so-called bath salts include mephedrone, methylone and 3,4-methylenedioxypyrovalerone (MDPV). Relatively little information about the pharmacology and addiction potential of these drugs is available. We used the conditioned place preference (CPP) paradigm to explore the reinforcing effects of three different synthetic cathinones. The primary aim of this study was to investigate whether mephedrone, methylone and MDPV induce CPP in mice. The secondary aims were to investigate a possible dose-response CPP and whether the synthetic cathinones induce higher CPP than amphetamine at equal dose. C57BL/6 mice were conditioned to mephedrone, methylone, MDPV and amphetamine at doses of 0.5, 2, 5, 10 or 20 mg/kg (i.p.). During the conditioning, the mice received two training sessions per day for 4 days. All four tested drugs showed a significant place preference compared with controls. Mice conditioned with MDPV (5 and 10 mg/kg) displayed a greater preference score compared to mice conditioned with amphetamine (5 and 10 mg/kg). Our findings show that mephedrone, methylone and MDPV produce CPP equal or higher than amphetamine strongly suggesting addictive properties. Given the public health concern of abuse, future pharmacological studies are necessary to fully understand the effects of these drugs.

Topics: Amphetamine; Animals; Benzodioxoles; Conditioning, Psychological; Dose-Response Relationship, Drug; Male; Methamphetamine; Mice; Mice, Inbred C57BL; Pyrrolidines; Synthetic Cathinone

The street drug "bath salts" are psychoactive mixtures of cathinone derivatives. We report 3 cases of disseminated Staphylococcus aureus infection with cardiac involvement (2 endocarditis and 1 pericarditis), secondary to intravenous bath salts use.

Topics: Adult; Alkaloids; Bacteremia; Designer Drugs; Endocarditis, Bacterial; Female; Humans; Illicit Drugs; Male; Methamphetamine; Pericarditis; Staphylococcal Infections; Staphylococcus aureus; Substance Abuse, Intravenous

Abuse of psychogenic substances sold as "bath salts" and "plant food" has escalated in recent years in the United States (USA). Previous reports suggest regional differences in the primary active β-keto phenylalkylamines found in these products and the corresponding signs and symptoms reported after exposure. Currently, there are only limited studies describing the clinical effects associated with reported "bath salts" exposure in the USA. This study describes the clinical effects associated with "bath salt" and "plant food" exposures as reported to the poison center serving the state of North Carolina (Carolinas Poison Center). We performed a retrospective review of the Carolinas Poison Center database for all cases of reported human exposure to "bath salt" and "plant food" products from 2010 to 2011 with specific attention to clinical effects and routes of exposure. Additionally, we reviewed therapies used, trended the volume of exposure cases reported over the study period, and evaluated the distribution of calls within state counties using descriptive statistics. Carolinas Poison Center received 485 total calls and 409 reported exposure calls regarding "bath salt" or "plant food" products between January of 2010 and December of 2011. The peak of reported exposures occurred in May of 2011. Clinical effects commonly reported in the exposure cases generated from these calls included tachycardia (53.3 %, n = 218), agitated/irritable (50.4 %, n = 206), hallucination/delusions (26.7 %, n = 109), and hypertension (25.2 %, n = 103). In addition to intravenous fluids, common therapies included benzodiazepines (46.0 %, n = 188), sedation (13.4 %, n = 55), alkalinization (3.90 %, n = 16), antihistamine (4.16 %, n = 17), and intubation (3.67 %, n = 15). Haloperidol was the antipsychotic agent used most often to treat agitation (n = 40). Serious complications associated with reported exposure to "bath salt" and "plant food" products included rhabdomyolysis, renal failure, excited delirium syndrome, and death. While treatments have not been empirically determined, sedation with benzodiazepines, aggressive cooling for hyperthermic patients, and use of small doses of antipsychotics for choreoathetoid movements not controlled with benzodiazepines are not likely to be harmful.

Topics: Adult; Baths; Benzodioxoles; Databases, Factual; Designer Drugs; Dietary Supplements; Female; Humans; Illicit Drugs; Male; Methamphetamine; Middle Aged; North Carolina; Phenethylamines; Plant Preparations; Poison Control Centers; Psychotropic Drugs; Pyrrolidines; Retrospective Studies; Substance Abuse Detection; Substance-Related Disorders; Synthetic Cathinone; Young Adult

The use of cathinone-derivative designer drugs methylone and mephedrone has increased rapidly in recent years. Our aim was to investigate the possible long-term effects of these drugs on a range of behavioral tests in mice. Further, we investigated the long-term effects of these drugs on brain neurochemistry in both rats and mice.. We treated animals with a binge-like regimen of methylone or mephedrone (30 mg/kg, twice daily for 4 days) and, starting 2 weeks later, we performed behavioral tests of memory, anxiety and depression and measured brain levels of dopamine (DA), serotonin (5-HT), their metabolites and norepinephrine (NE). 5-HT and DA transporter (5-HTT and DAT) levels were also measured in rats by [(3)H]paroxetine and [(3)H]mazindol binding.. Mephedrone reduced working memory performance in the T-maze spontaneous alternation task but did not affect neurotransmitter levels aside from a 22% decrease in striatal homovanillic acid (HVA) levels in mice. Methylone had little effect on behavior or neurotransmitter levels in mice but produced a widespread depletion of 5-HT and 5-HTT levels in rats.. Both methylone and mephedrone appeared to have a long-term effect on either behavioral or biochemical gauges of neurotoxicity in rodents.

Topics: Animals; Anxiety; Brain; Depression; Designer Drugs; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Hindlimb Suspension; Male; Maze Learning; Memory Disorders; Methamphetamine; Mice; Mice, Inbred C57BL; Norepinephrine; Radioligand Assay; Rats; Rats, Wistar; Serotonin; Serotonin Plasma Membrane Transport Proteins

This paper reports the development of arrays of capillary-based low-temperature plasma (LTP) probes for direct sample analysis. These probe arrays allow a higher surface area to be analyzed, increasing the throughput in large sample analysis. Validation of these arrays was performed on illicit, cathinone-based drugs marketed as 'bath salts'.. LTP arrays consisting of 1, 7, and 19 probes were constructed with quartz capillaries and held together with silver epoxy resin adhesive. Three drugs, mephedrone, methylone and methylenedioxypyrovalerone, were analyzed with each plasma ion source and an ion trap mass spectrometer in full MS and in MS/MS positive ion mode. Chemical and thermal footprints were determined for each source. A reactive probe design was used to inject trifluoroacetic anhydride directly into the plasma stream for on-line derivatization.. Small LTP probes and bundled arrays provide low picogram level limits of detection for mephedrone, methylone and methylenedioxypyrovalerone. Bundling the probes together in larger arrays increases the surface area analyzed by a factor of ten, while maintaining surface temperatures below 40 °C. Selectivity towards mephedrone and methylone was increased using trifluoracetylation under ambient ionization conditions.. Low-temperature plasma ionization sources allow rapid detection of illicit 'bath salt' drugs in low amounts. The sources have a larger sampling area that allows faster detection of each analyte, and selectivity towards the selected drug is enhanced by adding reagents directly into the plasma stream.

Topics: Benzodioxoles; Cold Temperature; Illicit Drugs; Limit of Detection; Mass Spectrometry; Methamphetamine; Models, Chemical; Plasma Gases; Pyrrolidines; Reproducibility of Results; Synthetic Cathinone

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.

Topics: 1-Methyl-4-phenylpyridinium; Analysis of Variance; Animals; Chromatography, High Pressure Liquid; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Electrochemistry; Hallucinogens; In Vitro Techniques; Locomotion; Male; Membrane Transport Proteins; Methamphetamine; Microdialysis; N-Methyl-3,4-methylenedioxyamphetamine; Norepinephrine Plasma Membrane Transport Proteins; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Serotonin; Synaptosomes; Time Factors; Tritium

Psychoactive bath salts are a relatively new group of designer drugs sold as tablets, capsules, or powder and pur-chased in places such as tobacco and convenience stores, gas stations, head shops, and the Internet. Bath salts are stimulant agents that mimic cocaine,lysergic acid diethylamide, methamphetamine, or methylenedioxymethamphetamine (ecstasy). The most common bath salts are the cathinone derivatives 3,4-methylenedioxypyrovalerone(MDPV), 4-methylmethcathinone(mephedrone), and 3,4-methylenedioxy-N-methylcathinone (methylone). The drugs cause intense stimulation, eu-phoria, elevated mood, and a pleasurable "rush" Tachycardia, hypertension,peripheral constriction, chest pain, hallucinations, paranoia, erratic behavior,inattention, lack of memory of substance use, and psychosis have been observed in those who have used bath salts. The U.S. Drug Enforcement Administration recently exercised an emergency authority to name three key ingredients in bath salts as Schedule I, thereby making them illegal to possess or sell in the United States. Nursing implications related to both clinical and educational settings are discussed.

Topics: Benzodioxoles; Central Nervous System Stimulants; Cross-Sectional Studies; Designer Drugs; Drug and Narcotic Control; Female; Humans; Illicit Drugs; Male; Methamphetamine; Middle Aged; Paranoid Disorders; Psychoses, Substance-Induced; Pyrrolidines; Substance Abuse Detection; Substance-Related Disorders; Synthetic Cathinone

Here, we have compared the neurochemical profile of three new cathinones, butylone, mephedrone and methylone, in terms of their potential to inhibit plasmalemmal and vesicular monoamine transporters. Their interaction with 5-HT and dopamine receptors and their psychostimulant effect was also studied.. Locomotor activity was recorded in mice following different doses of cathinones. Monoamine uptake assays were performed in purified rat synaptosomes. Radioligand-binding assays were carried out to assess the affinity of these compounds for monoamine transporters or receptors.. Butylone, mephedrone and methylone (5-25 mg·kg(-1) ) caused hyperlocomotion, which was prevented with ketanserin or haloperidol. Methylone was the most potent compound inhibiting both [(3) H]5-HT and [(3) H]dopamine uptake with IC(50) values that correlate with its affinity for dopamine and 5-HT transporter. Mephedrone was found to be the cathinone derivative with highest affinity for vesicular monoamine transporter-2 causing the inhibition of dopamine uptake. The affinity of cathinones for 5-HT(2A) receptors was similar to that of MDMA.. Butylone and methylone induced hyperlocomotion through activating 5-HT(2A) receptors and increasing extra-cellular dopamine. They inhibited 5-HT and dopamine uptake by competing with substrate. Methylone was the most potent 5-HT and dopamine uptake inhibitor and its effect partly persisted after withdrawal. Mephedrone-induced hyperlocomotion was dependent on endogenous 5-HT. Vesicular content played a key role in the effect of mephedrone, especially for 5-HT uptake inhibition. The potency of mephedrone in inhibiting noradrenaline uptake suggests a sympathetic effect of this cathinone.

Topics: 3,4-Methylenedioxyamphetamine; Animals; Brain; Carrier Proteins; Central Nervous System Stimulants; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Drug; Haloperidol; Ketanserin; Male; Methamphetamine; Mice; Molecular Structure; Motor Activity; Norepinephrine; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists; Synaptosomes

Drugs derived from amphetamine, methamphetamine and their methylenedioxy- analogues, although being sold as plant food or bath salts, are being used as legal alternatives to scheduled amphetamine stimulants. These products often contain methylone, mephedrone and methylenedioxypyrovalerone (MDPV)--three amphetamine derivatives shown to have strong pharmacological effects. Four postmortem cases were analyzed for methylone, mephedrone and MDPV, with drug levels quantitated in multiple biological matrices. All four cases had detectable levels of methylone, with heart blood concentrations of 0.740, 0.118, 0.060 and 1.12 mg/L. Analysis of several tissue samples shows that methylone does not sequester in a particular tissue type after death. The average liver-to-blood ratio was 2.68. Two cases also had MDPV present, but insufficient data were collected to formulate a hypothesis on postmortem sequestration or redistribution. Two different extraction methods, as well as analysis of derivatized and underivatized methylone, show that the drug is suitable for analysis in either method. The cases are believed to show one instance of chronic methylone use, with a urine concentration of 38 mg/L.

Topics: Adult; Algorithms; Benzodioxoles; Central Nervous System Stimulants; Female; Humans; Liver; Male; Methamphetamine; Pyrrolidines; Synthetic Cathinone; Tissue Distribution; Young Adult

Topics: Administration, Inhalation; Adult; Alkaloids; Catha; Central Nervous System Stimulants; Diagnosis, Differential; Emergency Service, Hospital; Female; Humans; Mental Status Schedule; Methamphetamine; Psychoses, Substance-Induced; Pyrrolidines; Serotonin; Serotonin Syndrome

In recent years, a new class of designer drugs has appeared on the drugs of abuse market in many countries, namely, the so-called beta-keto (bk) designer drugs such as mephedrone (bk-4-methylmethamphetamine), butylone (bk-MBDB), and methylone (bk-MDMA). The aim of the present study was to identify the metabolites of mephedrone in rat and human urine using GC-MS techniques and to include mephedrone, butylone, and methylone within the authors' systematic toxicological analysis (STA) procedure. Six phase I metabolites of mephedrone were detected in rat urine and seven in human urine suggesting the following metabolic steps: N-demethylation to the primary amine, reduction of the keto moiety to the respective alcohol, and oxidation of the tolyl moiety to the corresponding alcohols and carboxylic acid. The STA procedure allowed the detection of mephedrone, butylone, methylone, and their metabolites in urine of rats treated with doses corresponding to those reported for abuse of amphetamines. Besides macro-based data evaluation, an automated evaluation using the automated mass spectral deconvolution and identification system was performed. Mephedrone and butylone could be detected also in human urine samples submitted for drug testing. Assuming similar kinetics in humans, the described STA procedure should be suitable for proof of an intake of the bk-designer drugs in human urine.

Topics: 3,4-Methylenedioxyamphetamine; Amphetamines; Animals; Designer Drugs; Gas Chromatography-Mass Spectrometry; Humans; Male; Methamphetamine; Rats; Rats, Wistar

The use of "Head Shop" compounds has received much media attention lately. There is very little research in the current literature with regard to the extent of the usage of these substances amongst the drug using population in Ireland. We conducted a study to examine the extent of the usage of Mephedrone, Methylone and BZP amongst attendees of Methadone maintenance programs at the DTCB. Two hundred and nine samples in total were tested. The results showed significant usage of these compounds amongst this cohort of drug users, with 29 (13.9%) of samples tested being positive for Mephedrone, 7 (3.3%) positive for Methylone and 1 (0.5%) positive for BZP.

Topics: Chromatography, Liquid; Female; Humans; Illicit Drugs; Ireland; Male; Mass Screening; Mass Spectrometry; Methamphetamine; Piperazines; Substance Abuse Treatment Centers; Substance-Related Disorders