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David M. Wood - One of the best experts on this subject based on the ideXlab platform.
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Chapter 9 – Mephedrone
Novel Psychoactive Substances, 2013Co-Authors: David M. Wood, Paul I. DarganAbstract:Mephedrone (4-methylmethcathinone) is one of a number of synthetic cathinones that have emerged as novel psychoactive substances (NPS) since 2005/6. This chapter will focus on Mephedrone as it is the most widely used cathinone and the one for which there is the most published literature. Mephedrone is most commonly available in powder form, but it is also available as tablets and capsules. The most common routes of use are nasal insufflation and oral ingestion: there are also reports of use by rectal insertion and intravenous/intramuscular injection. Users commonly report re-dosing during single-use sessions with total doses per session typically being 0.5–7.0 g. Data on population level prevalence of use of Mephedrone is only available from the UK from 2010; this shows similar prevalence of use to ecstasy. A number of subpopulation surveys, mainly in the UK, elsewhere in Europe and Australia, have investigated the prevalence of use of Mephedrone in other groups and shown that it appears to be more commonly used in the men who have sex with men population, in children of school age and those who frequent the night-time economy; although there have been regional differences in use patterns in some of these studies. There is limited data available on the pharmacokinetics of Mephedrone, other than on its metabolism which has been investigated in both animal and human studies. A number of recent animal studies have investigated mechanisms of action of Mephedrone. These suggest that, overall, Mephedrone has similar actions both at a cellular and whole animal model level to other stimulant recreational drugs such as cocaine and amphetamine. Data is available on the patterns of acute toxicity of Mephedrone from user reports on Internet drugs discussion fora, from calls to Poisons Information Services and from published case reports/case series of presentations to hospital with acute Mephedrone toxicity (including one analytically confirmed series). Triangulation of data from these sources shows that Mephedrone is associated with sympathomimetic (stimulant) toxicity in a similar pattern to that seen with 3,4-methylenedioxymethamphetamine (MDMA), amphetamine or cocaine. There have Mephedrone-related deaths reported from the UK, Sweden, Netherland and Italy; there are also reports of Mephedrone detection in fatalities from other countries in Europe and the USA, although it is difficult to be certain of the role of Mephedrone in many of these fatalities. Data from both animal studies and largely anecdotal human reports suggests that Mephedrone can be associated with psychological dependence, similar to that seen with other stimulant recreational drugs such as MDMA and cocaine.
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emergency department presentations in determining the effectiveness of drug control in the united kingdom Mephedrone 4 methylmethcathinone control appears to be effective using this model
Emergency Medicine Journal, 2013Co-Authors: David M. Wood, S L Greene, Paul I. DarganAbstract:Mephedrone (4-methylmethcathinone) and related cathinones were controlled in the United Kingdom on 16 April 2010. An analysis of presentations to the emergency department of patients with acute toxicity related to the use of Mephedrone demonstrated that there was a peak in presentations prior to and a significant fall in presentations following the control of Mephedrone. This suggests that the control of Mephedrone in the United Kingdom may have been effective in reducing the acute harm associated with the drug.
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Mephedrone (4-methylmethcathinone): what is new in our understanding of its use and toxicity.
Progress in neuro-psychopharmacology & biological psychiatry, 2012Co-Authors: David M. Wood, Paul I. DarganAbstract:Mephedrone (4-methylmethcathinone) is a synthetic cathinone that has been used as a recreational drug in Europe and elsewhere in the world since 2007. In addition to published scientific papers there are a number of different data sources available which provide information on the sources, availability and prevalence of use of Mephedrone. Whilst there are no formal human studies to determine the acute toxicity of Mephedrone, there is a range of different levels of data available which describe the acute toxicity of Mephedrone. These include user Internet discussion fora, sub-population level surveys of user previous experiences of acute toxicity and individual case reports and case series of toxicity related to both self-reported and analytically confirmed Mephedrone use. In this review article we describe how through the process of data triangulation using a combination of these different sources, it is possible to develop an understanding of the acute toxicity of Mephedrone. This demonstrates that Mephedrone has a pattern of acute toxicity that is similar to other stimulant drugs such as MDMA, amphetamine and cocaine.
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the pharmacology and toxicology of the synthetic cathinone Mephedrone 4 methylmethcathinone
Drug Testing and Analysis, 2011Co-Authors: Paul I. Dargan, David M. Wood, Roumen Sedefov, Ana GallegosAbstract:Mephedrone (4-methylmethcathinone) is a synthetic cathinone that is used as a recreational drug. It has been available since 2007 but its availability and use increased significantly during 2009 and 2010. In this review article we will summarize the availableliteratureonthesources,availability,andprevalenceoftheuseofMephedrone.Wewillalsodiscussthepharmacology of Mephedrone, the patterns of acute toxicity associated with its use, the reports of fatalities associated with its use, and the potential for Mephedrone dependence. Copyright c � 2011 John Wiley & Sons, Ltd.
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Case series of individuals with analytically confirmed acute Mephedrone toxicity.
Clinical toxicology (Philadelphia Pa.), 2010Co-Authors: David M. Wood, Susannah Davies, S L Greene, Jenny Button, David W. Holt, John Ramsey, Paul I. DarganAbstract:Context. Previous reports of acute toxicity/harm associated with Mephedrone use have been based on self-reported Mephedrone use; toxicological screening has not been undertaken in these cases to determine whether Mephedrone has been used. Objective. To report the first case series of analytically confirmed Mephedrone-related acute toxicity. Materials and methods. Serum samples were collected from individuals presenting to an emergency department (ED) with acute toxicity related to self-reported Mephedrone use. Toxicological analysis, by gas-chromatography coupled with mass-spectrometry and liquid chromatography with tandem mass-spectrometry was performed to qualitatively confirm Mephedrone use. Symptoms/signs of acute Mephedrone toxicity and basic physiological parameters were extracted from the routine ED records. Results. Acute Mephedrone-related toxicity was analytically confirmed in seven male patients; the mean ± SD age was 24.6 ± 6.5 years (range 16–36 years). Agitation (four patients) was the most ...
Paul I. Dargan - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of Mephedrone Enantiomers in Whole Blood after a Controlled Intranasal Administration to Healthy Human Volunteers.
Pharmaceuticals (Basel Switzerland), 2020Co-Authors: Joanna Czerwinska, Claire George, Paul I. Dargan, Mark C. Parkin, Andrew T. Kicman, Agostino Cilibrizzi, Vincenzo AbbateAbstract:Mephedrone, which is one of the most popular synthetic cathinones, has one chiral centre and thus exists as two enantiomers: R-(+)-Mephedrone and S-(−)-Mephedrone. There are some preliminary data suggesting that the enantiomers of Mephedrone may display enantioselective pharmacokinetics and exhibit different neurological effects. In this study, enantiomers of Mephedrone were resolved via chromatographic chiral recognition and the absolute configuration was unambiguously determined by a combination of elution order and chiroptical analysis (i.e., circular dichroism). A chiral liquid chromatography tandem mass spectrometry method was fully validated and was applied to the analysis of whole blood samples collected from a controlled intranasal administration of racemic Mephedrone hydrochloride to healthy male volunteers. Both enantiomers showed similar kinetics, however, R-(+)-Mephedrone had a greater mean Cmax of 48.5 ± 11.9 ng/mL and a longer mean half-life of 1.92 ± 0.27 h compared with 44.6 ± 11.8 ng/mL and 1.63 ± 0.23 h for S-(−)-Mephedrone, respectively. Moreover, R-(+)-Mephedrone had a lower mean clearance and roughly 1.3 times greater mean area under the curve than S-(−)-Mephedrone. Significant changes in the enantiomeric ratio over time were observed, which suggest that the analytes exhibit enantioselective pharmacokinetics. Even though the clinical significance of this finding is not yet fully understood, the study confirms that the chiral nature, and consequently the enantiomeric purity of Mephedrone, can be a crucial consideration when interpreting toxicological results.
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Stability of Mephedrone and five of its phase I metabolites in human whole blood.
Drug testing and analysis, 2018Co-Authors: Joanna Czerwinska, Claire George, Paul I. Dargan, Mark C. Parkin, Andrew T. Kicman, Vincenzo AbbateAbstract:Mephedrone is a new psychoactive substance known to be unstable in biological matrices stored at room temperature or refrigerated. While the instability of Mephedrone has been investigated before, there is currently no data regarding the stability of Mephedrone metabolites. In this study, a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of Mephedrone and five of its phase I metabolites (dihydro-Mephedrone, nor-Mephedrone, hydroxytolyl-Mephedrone, 4-carboxy-Mephedrone and dihydro-nor-Mephedrone) in human whole blood has been developed and validated. Samples were extracted by a mixed mode solid-phase extraction and analyzed on a pentafluorophenylpropyl column. The method was successfully validated for selectivity, linearity (0.2-2 to 10-100 ng/mL), limits of detection (50-500 pg/mL) and quantification (200-2000 pg/mL), precision (0.924-8.27%), accuracy (86.6-115%), carryover, recovery (32.5-88.3%), and matrix effects (71.0-108%). Analyte stability in human whole blood preserved with sodium fluoride/potassium oxalate was assessed at +4°C and -20°C after 24 hours, 48 hours, 4 days, and 10 days of storage. Instability was observed in samples stored at +4°C: nor-Mephedrone and 4-carboxy-Mephedrone lost 40.2 ± 6.7% and 48.1 ± 4.8%, respectively, of their initial concentration at low concentration level and 33.8 ± 4.2% and 44.6 ± 6.5%, respectively, at high concentration level after 10 days. All analytes were more stable at -20°C where the highest loss of 22.6 ± 6.9% was observed for 4-carboxy-Mephedrone after 10 days. This is the first time stability of Mephedrone metabolites in human whole blood has been assessed, indicating -20°C to be the recommended storage condition for all analytes in clinical settings.
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Chapter 9 – Mephedrone
Novel Psychoactive Substances, 2013Co-Authors: David M. Wood, Paul I. DarganAbstract:Mephedrone (4-methylmethcathinone) is one of a number of synthetic cathinones that have emerged as novel psychoactive substances (NPS) since 2005/6. This chapter will focus on Mephedrone as it is the most widely used cathinone and the one for which there is the most published literature. Mephedrone is most commonly available in powder form, but it is also available as tablets and capsules. The most common routes of use are nasal insufflation and oral ingestion: there are also reports of use by rectal insertion and intravenous/intramuscular injection. Users commonly report re-dosing during single-use sessions with total doses per session typically being 0.5–7.0 g. Data on population level prevalence of use of Mephedrone is only available from the UK from 2010; this shows similar prevalence of use to ecstasy. A number of subpopulation surveys, mainly in the UK, elsewhere in Europe and Australia, have investigated the prevalence of use of Mephedrone in other groups and shown that it appears to be more commonly used in the men who have sex with men population, in children of school age and those who frequent the night-time economy; although there have been regional differences in use patterns in some of these studies. There is limited data available on the pharmacokinetics of Mephedrone, other than on its metabolism which has been investigated in both animal and human studies. A number of recent animal studies have investigated mechanisms of action of Mephedrone. These suggest that, overall, Mephedrone has similar actions both at a cellular and whole animal model level to other stimulant recreational drugs such as cocaine and amphetamine. Data is available on the patterns of acute toxicity of Mephedrone from user reports on Internet drugs discussion fora, from calls to Poisons Information Services and from published case reports/case series of presentations to hospital with acute Mephedrone toxicity (including one analytically confirmed series). Triangulation of data from these sources shows that Mephedrone is associated with sympathomimetic (stimulant) toxicity in a similar pattern to that seen with 3,4-methylenedioxymethamphetamine (MDMA), amphetamine or cocaine. There have Mephedrone-related deaths reported from the UK, Sweden, Netherland and Italy; there are also reports of Mephedrone detection in fatalities from other countries in Europe and the USA, although it is difficult to be certain of the role of Mephedrone in many of these fatalities. Data from both animal studies and largely anecdotal human reports suggests that Mephedrone can be associated with psychological dependence, similar to that seen with other stimulant recreational drugs such as MDMA and cocaine.
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emergency department presentations in determining the effectiveness of drug control in the united kingdom Mephedrone 4 methylmethcathinone control appears to be effective using this model
Emergency Medicine Journal, 2013Co-Authors: David M. Wood, S L Greene, Paul I. DarganAbstract:Mephedrone (4-methylmethcathinone) and related cathinones were controlled in the United Kingdom on 16 April 2010. An analysis of presentations to the emergency department of patients with acute toxicity related to the use of Mephedrone demonstrated that there was a peak in presentations prior to and a significant fall in presentations following the control of Mephedrone. This suggests that the control of Mephedrone in the United Kingdom may have been effective in reducing the acute harm associated with the drug.
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Mephedrone (4-methylmethcathinone): what is new in our understanding of its use and toxicity.
Progress in neuro-psychopharmacology & biological psychiatry, 2012Co-Authors: David M. Wood, Paul I. DarganAbstract:Mephedrone (4-methylmethcathinone) is a synthetic cathinone that has been used as a recreational drug in Europe and elsewhere in the world since 2007. In addition to published scientific papers there are a number of different data sources available which provide information on the sources, availability and prevalence of use of Mephedrone. Whilst there are no formal human studies to determine the acute toxicity of Mephedrone, there is a range of different levels of data available which describe the acute toxicity of Mephedrone. These include user Internet discussion fora, sub-population level surveys of user previous experiences of acute toxicity and individual case reports and case series of toxicity related to both self-reported and analytically confirmed Mephedrone use. In this review article we describe how through the process of data triangulation using a combination of these different sources, it is possible to develop an understanding of the acute toxicity of Mephedrone. This demonstrates that Mephedrone has a pattern of acute toxicity that is similar to other stimulant drugs such as MDMA, amphetamine and cocaine.
Peter J. Winsauer - One of the best experts on this subject based on the ideXlab platform.
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Effects of cocaine on the discriminative stimulus and reinforcing effects of Mephedrone in male rats.
Psychopharmacology, 2018Co-Authors: Laura L. Erwin, Mark R. Nilges, Zachary B. Bondy, Peter J. WinsauerAbstract:Abuse of cathinones has been a worldwide health concern for some time. Their chemical structures and wide variation in pharmacodynamic effects have led to clinical and preclinical effects that can be both similar to and different from other psychoactive substances such as methylenedioxymethamphetamine (MDMA), methamphetamine, and cocaine. The present study examined the discriminative stimulus and reinforcing effects of Mephedrone to further characterize the behavioral and pharmacological profile of this first-generation substituted methcathinone. Rats were trained to discriminate Mephedrone (3.2 mg/kg) from saline under a fixed-ratio 20 (FR-20) schedule of food presentation. After establishing dose-effect curves for increasing cumulative doses of Mephedrone, substitution tests were conducted with bupropion (5.6–32 mg/kg), cocaine (1.8–18 mg/kg), morphine (0.56–10 mg/kg), and amitriptyline (3.2–32 mg/kg). In addition, cocaine (3.2–18 mg/kg) and the serotonin type-2 (5-HT2) receptor antagonist ritanserin (1, 3.2, and 10 mg/kg) were administered prior to the cumulative doses of Mephedrone. Lastly, varying infusion doses of cocaine were substituted for Mephedrone in subjects trained to self-administer Mephedrone, and varying infusion doses of Mephedrone were substituted for cocaine in subjects trained to self-administer cocaine to assess the importance of drug history on the reinforcing effects of Mephedrone. Of the drugs tested, cocaine had the highest level of Mephedrone-lever responding when administered alone (73.5%). In combination with Mephedrone, cocaine shifted the Mephedrone dose-effect curve upwards in an infra-additive manner. Ritanserin had a small, but non-significant, effect on Mephedrone’s discriminative stimulus effects. An extensive history (baseline) of cocaine self-administration increased Mephedrone self-administration compared to that obtained in Mephedrone-trained subjects, whereas a baseline of Mephedrone self-administration decreased cocaine self-administration compared to that obtained in cocaine-trained subjects. The similarity between the discriminative stimulus effects of cocaine and Mephedrone in male rats suggests an important overlap and the relative importance of the dopamine (DAT) and serotonin (SERT) transporters. The self-administration data suggest that Mephedrone is less reinforcing than cocaine, but that a history of responding for cocaine can increase the reinforcing effects of Mephedrone.
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Atypical binding at dopamine and serotonin transporters contribute to the discriminative stimulus effects of Mephedrone
Neuropharmacology, 2017Co-Authors: Alyssa F. Delarge, Laura L. Erwin, Peter J. WinsauerAbstract:Abstract Mephedrone (4-methylmethcathinone), a constituent of the recreational substances known as “bath salts”, is a synthetic cathinone that can produce auditory and visual hallucinations, as well as problematic cardiovascular effects. This study compared the discriminative stimulus effects of Mephedrone (0.32–10 mg/kg) with other prototypical drugs of abuse: cocaine (0.56–32 mg/kg), d -amphetamine (0.18–3.2 mg/kg), ketamine (1.8–18 mg/kg), phencyclidine (PCP, 1–5.6 mg/kg), heroin (1–10 mg/kg), 2,5-dimethoxy-4-iodoamphetamine (R-DOI, 0.1–1 mg/kg), Δ 9 -tetrahydrocannabinol (Δ 9− THC 0.56–5.6 mg/kg), 3,4-methylenedioxyamphetamine (MDA, 0.32–5.6 mg/kg), methylphenidate (1–10 mg/kg), and 3,4-methylenedioxypyrovalerone (MDPV, 0.56–5.6 mg/kg). The discriminative stimulus effects of Mephedrone were also assessed after administration of the sigma receptor antagonist rimcazole (0.32–10 mg/kg), the relatively selective norepinephrine transporter (NET) inhibitor desipramine (1.8–18 mg/kg), and the selective serotonin transporter (SERT) inhibitor fluoxetine (1–18 mg/kg). Initially, rats were trained to discriminate an intraperitoneal injection of Mephedrone (3.2 mg/kg) from saline under a fixed-ratio 20 schedule of food presentation. Following training, cumulative doses of Mephedrone and the other drugs were administered to test for substitution (80% drug-lever responding). Of the drugs tested, including those that were tested in combination with Mephedrone (i.e., rimcazole, desipramine, and fluoxetine), only cocaine fully substituted for Mephedrone without substantially decreasing response rate. In addition, the three drugs administered in combination with Mephedrone shifted the cumulative dose-effect curves leftward (percent drug-lever responding) and down (response rate), although fluoxetine did so in a dose-dependent manner ranging from antagonism to potentiation. In summary, the discriminative stimulus effects of Mephedrone were most similar to those for the central nervous system (CNS) stimulant, cocaine, and SERT and DAT activity were necessary for these effects.
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The Discriminative-Stimulus Effects of Mephedrone in Comparison with Other Drugs of Abuse
The FASEB Journal, 2015Co-Authors: Alyssa F. Delarge, Peter J. WinsauerAbstract:Mephedrone (4-methylmethcathinone) is one of the major constituents of the recreational drug, “bath salts”. It is a synthetic cathinone and potent psychostimulant that has been reported to cause auditory and visual hallucinations. The purpose of this study was to compare the discriminative stimulus effects of Mephedrone alone with those of other prototypical drugs of abuse, such as cocaine, delta-9-tetrahydrocannabinol (THC), phencyclidine (PCP), and 2,5-dimethoxy-4-iodoamphetamine (DOI). Rats were trained to discriminate an intraperitoneal injection of Mephedrone from saline under a fixed-ratio 20 schedule of food presentation. The final training dose of Mephedrone was 3.2 mg/kg and it was reliably discriminated from saline by all subjects. Following training, substitution tests indicated that cocaine (0.56-32 mg/kg) fully substituted for Mephedrone (0.32-10 mg/kg) by producing over 80% Mephedrone-lever responding, whereas THC (0.56-10 mg/kg), PCP (1-5.6 mg/kg) and DOI(0.1-1 mg/kg) produced a maximum of ...
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Estradiol administration to ovariectomized rats potentiates Mephedrone-induced disruptions of nonspatial learning.
Journal of the experimental analysis of behavior, 2014Co-Authors: Peter F. Weed, Stuart T. Leonard, Ananthakrishnan Sankaranarayanan, Peter J. WinsauerAbstract:Mephedrone (4-methylmethcathinone) has been found in several over-the-counter products that are abused by humans, but very little is known about its behavioral effects and abuse liability. The present study examined the effects of Mephedrone (1-10 mg/kg) on learning in female rats, as well as its interaction with the ovarian hormone estradiol. More specifically, female rats were trained to respond under a multiple schedule of repeated acquisition and performance of response sequences and then ovariectomized. Following ovariectomy, Mephedrone dose-effect curves were obtained during periods of 17β-estradiol administration and periods without estradiol administration. Unlike Mephedrone, which was administered acutely (i.p.) before the experimental sessions, 17β-estradiol was administered via subcutaneous Silastic capsules containing 25% 17β-estradiol and 75% cholesterol. In general, Mephedrone produced dose-dependent rate-decreasing and error-increasing effects in the acquisition and performance components of the schedule in all subjects. However, when estradiol was present, three of the four rats were more sensitive to the rate-decreasing effects of Mephedrone, and all of the subjects were more sensitive to its error-increasing effects. These data indicate that estradiol can potentiate the disruptive effects of Mephedrone on both the acquisition and performance of complex behavior in female rats.
Magí Farré - One of the best experts on this subject based on the ideXlab platform.
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Acute Pharmacological Effects of Oral and Intranasal Mephedrone: An Observational Study in Humans.
Pharmaceuticals (Basel Switzerland), 2021Co-Authors: Esther Papaseit, Eulàlia Olesti, Rafael De La Torre, Clara Pérez-mañá, Francina Fonseca, Marta Torrens, Marc Grifell, Mireia Ventura, Magí FarréAbstract:Mephedrone (4-methylmethcathinone) is a synthetic cathinone with psychostimulant properties which remains one of the most popular new psychoactive substances (NPS). It is frequently used orally and/or intranasally. To date, no studies have evaluated the acute effects and pharmacokinetics after self-administration of Mephedrone orally (ingestion) and intranasally (insufflation) in naturalistic conditions. An observational study was conducted to assess and compare the acute pharmacological effects, as well as the oral fluid (saliva) concentrations of Mephedrone self-administered orally and intranasally. Ten healthy experienced drug users (4 females and 6 males) self-administered a single dose of Mephedrone, orally (n = 5, 100-200 mg; mean 150 mg) or intranasally (n = 5, 50-100 mg, mean 70 mg). Vital signs (blood pressure, heart rate, and cutaneous temperature) were measured at baseline (0), 1, 2, and 4 h after self-administration. Each participant completed subjective effects questionnaires: A set of Visual Analogue Scales (VAS), the 49-item Addiction Research Centre Inventory (ARCI), and Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 1, 2, and 4 h after self-administration. Oral fluid and urine were collected during 4 h. Both routes of Mephedrone self-administration enhanced ratings of euphoria and well-being effects and increased cardiovascular effects in humans. Although it was at times assessed that the oral route produced greater and larger effects than the intranasal one, concentrations of Mephedrone in oral fluid and also the total amount of Mephedrone and metabolites in urine showed that concentrations of Mephedrone are considerably higher when self-administered intranasally in comparison to orally. Controlled clinical trials are needed to confirm our observational results.
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dose response pharmacological study of Mephedrone and its metabolites pharmacokinetics serotoninergic effects and impact of cyp2d6 genetic variation
Clinical Pharmacology & Therapeutics, 2019Co-Authors: Eulàlia Olesti, Magí Farré, Esther Papaseit, Mitona Pujadas, Marta Torrens, Marcel Li Carbo, Clara Perezmana, Samanta Yuberolahoz, Óscar J. PozoAbstract:Mephedrone (MEPH), the most widely consumed synthetic cathinone, has been associated with acute toxicity episodes. The aim of this report was to study its metabolic disposition and the impact of genetic variation of CYP2D6 on MEPH metabolism, in a dose range compatible with its recreational use. A randomized, crossover, phase I clinical trial was performed. Subjects received 50 and 100 mg (n = 3) and 150 and 200 mg (n = 6) of Mephedrone and were genetically and phenotypically characterized for the CYP2D6 allelic variation. Our results showed a linear kinetics of Mephedrone at the dose range assayed: plasma concentrations, cardiovascular and subjective effects, and blood serotonin concentrations all correlated in a dose-dependent manner. Mephedrone metabolic disposition is mediated by CYP2D6. Mephedrone pharmacology presented a linear dose-dependence within the range of doses tested. The metabolism of Mephedrone by CYP2D6 implies that recreational users with no or low CYP2D6 functionality are exposed to unwanted acute toxicity episodes.
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Mephedrone Concentrations in Cases of Clinical Intoxication.
Current pharmaceutical design, 2018Co-Authors: Esther Papaseit, Eulàlia Olesti, Rafael De La Torre, Marta Torrens, Magí FarréAbstract:Background Mephedrone (4-methylmethcathinone, 4-MMC), a ring-substituted synthetic cathinone derivative has become established as a permanent illicit drug in the dynamic new psychoactive substances (NPS) scene. Objective This review summarizes current knowledge on Mephedrone concentrations in biological samples from cases of acute intoxications (fatal and non-fatal), pharmacokinetics studies, wastewater and anonymous pooled urine analysis in order to provide an overview of the reliable scientific knowledge on toxicokinetics of Mephedrone in humans. Method The PubMed® database complemented with Google Scholar® was systematically searched to find published cases of Mephedrone intoxications. The searches were done using the keyword "Mephedrone OR 4- methylmethcathinone" in association to each of the following strategies: i) "intoxication OR poisoning"; ii) "(blood OR serum OR plasma") OR "urine" OR ("saliva OR oral fluid") OR "hair"; iii) "forensic toxicology samples"; iv) "wastewater OR sewage OR pooled urine" and v) "toxicity OR death OR fatal". Results Since 2010, a total of 97 fatal cases and 57 non-fatal intoxication cases were identified that presented Mephedrone concentrations in human biological matrices attributed directly or indirectly to Mephedrone. Typical subjects involved were young male with concomitant use of other drugs (psychostimulants, cannabis, alcohol and other depressants). Mephedrone mean blood concentration from fatal cases was 2,663 ng/mL (range 51-22,000 ng/mL), from non-fatal cases was 166 ng/mL (range, 13-412 ng/mL), that resulted in a similar range from data found in controlled studies with no acute toxicity associated (135 ng/mL, range 52-218 ng/mL). Forensic epidemiology studies based on wastewater and anonymous pooled urine analysis point towards similar variations in use (nightclub scene) to those self-reported in surveys and questioners. Conclusion Mephedrone blood concentrations in cases of fatal intoxications were higher than in non-fatal cases. In both cases, great variability in Mephedrone concentration potentially attributable to interindividual differences in pharmacokinetics-pharmacodynamics and poly-drug use complicates the interpretation of the forensic toxicological analysis.
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Pharmacokinetics of Mephedrone and Its Metabolites in Human by LC-MS/MS
The AAPS Journal, 2017Co-Authors: Eulàlia Olesti, Magí Farré, Esther Papaseit, Aristotelis Krotonoulas, Mitona Pujadas, Rafael De La Torre, Óscar J. PozoAbstract:Mephedrone is a synthetic cathinone consumed as a recreational drug. Recently, it was identified several of its metabolites in vivo in humans but there is little information about its pharmacokinetics in plasma and urine. Although several analytical methods have been proposed for Mephedrone quantification in different matrices, none are available for its metabolites. Therefore, the aim of the study was to develop and validate an analytical method using liquid chromatography-tandem mass spectrometry for the quantification of Mephedrone, nor-Mephedrone, N -succinyl-nor-Mephedrone, 1′-dihydro-Mephedrone, and 4′-carboxy-Mephedrone. The method was validated in human plasma and urine and in rat brain homogenates. Six healthy male subjects, recreational users of new psychoactive substances, ingested 150 mg of Mephedrone within the context of a clinical trial. 4′-Carboxy-Mephedrone, followed by nor-Mephedrone, was the most abundant metabolites found in plasma. Dihydro-Mephedrone represented 10% of the amount of Mephedrone in plasma and N -succinyl-nor-Mephedrone was the metabolite eliminated with the longer half-life of 8.2 h. In urine, 4′-carboxy-Mephedrone was the main metabolite excreted with amounts recovered being about 10 times those of Mephedrone. Additionally, the validated method was used to test metabolite ability to cross the blood-brain barrier in vivo in rats with Mephedrone and nor-Mephedrone as the main active compounds present in the brain. The method described is useful for the determinations of Mephedrone and metabolites in biological samples. Graphical Abstract ᅟ
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pharmacokinetics of Mephedrone and its metabolites in human by lc ms ms
Aaps Journal, 2017Co-Authors: Eulàlia Olesti, Magí Farré, Esther Papaseit, Aristotelis Krotonoulas, Mitona Pujadas, Rafael De La Torre, Óscar J. PozoAbstract:Mephedrone is a synthetic cathinone consumed as a recreational drug. Recently, it was identified several of its metabolites in vivo in humans but there is little information about its pharmacokinetics in plasma and urine. Although several analytical methods have been proposed for Mephedrone quantification in different matrices, none are available for its metabolites. Therefore, the aim of the study was to develop and validate an analytical method using liquid chromatography-tandem mass spectrometry for the quantification of Mephedrone, nor-Mephedrone, N-succinyl-nor-Mephedrone, 1′-dihydro-Mephedrone, and 4′-carboxy-Mephedrone. The method was validated in human plasma and urine and in rat brain homogenates. Six healthy male subjects, recreational users of new psychoactive substances, ingested 150 mg of Mephedrone within the context of a clinical trial. 4′-Carboxy-Mephedrone, followed by nor-Mephedrone, was the most abundant metabolites found in plasma. Dihydro-Mephedrone represented 10% of the amount of Mephedrone in plasma and N-succinyl-nor-Mephedrone was the metabolite eliminated with the longer half-life of 8.2 h. In urine, 4′-carboxy-Mephedrone was the main metabolite excreted with amounts recovered being about 10 times those of Mephedrone. Additionally, the validated method was used to test metabolite ability to cross the blood-brain barrier in vivo in rats with Mephedrone and nor-Mephedrone as the main active compounds present in the brain. The method described is useful for the determinations of Mephedrone and metabolites in biological samples.
Eulàlia Olesti - One of the best experts on this subject based on the ideXlab platform.
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Acute Pharmacological Effects of Oral and Intranasal Mephedrone: An Observational Study in Humans.
Pharmaceuticals (Basel Switzerland), 2021Co-Authors: Esther Papaseit, Eulàlia Olesti, Rafael De La Torre, Clara Pérez-mañá, Francina Fonseca, Marta Torrens, Marc Grifell, Mireia Ventura, Magí FarréAbstract:Mephedrone (4-methylmethcathinone) is a synthetic cathinone with psychostimulant properties which remains one of the most popular new psychoactive substances (NPS). It is frequently used orally and/or intranasally. To date, no studies have evaluated the acute effects and pharmacokinetics after self-administration of Mephedrone orally (ingestion) and intranasally (insufflation) in naturalistic conditions. An observational study was conducted to assess and compare the acute pharmacological effects, as well as the oral fluid (saliva) concentrations of Mephedrone self-administered orally and intranasally. Ten healthy experienced drug users (4 females and 6 males) self-administered a single dose of Mephedrone, orally (n = 5, 100-200 mg; mean 150 mg) or intranasally (n = 5, 50-100 mg, mean 70 mg). Vital signs (blood pressure, heart rate, and cutaneous temperature) were measured at baseline (0), 1, 2, and 4 h after self-administration. Each participant completed subjective effects questionnaires: A set of Visual Analogue Scales (VAS), the 49-item Addiction Research Centre Inventory (ARCI), and Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 1, 2, and 4 h after self-administration. Oral fluid and urine were collected during 4 h. Both routes of Mephedrone self-administration enhanced ratings of euphoria and well-being effects and increased cardiovascular effects in humans. Although it was at times assessed that the oral route produced greater and larger effects than the intranasal one, concentrations of Mephedrone in oral fluid and also the total amount of Mephedrone and metabolites in urine showed that concentrations of Mephedrone are considerably higher when self-administered intranasally in comparison to orally. Controlled clinical trials are needed to confirm our observational results.
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Mephedrone and Alcohol Interactions in Humans.
Frontiers in pharmacology, 2020Co-Authors: Esther Papaseit, Eulàlia Olesti, Clara Pérez-mañá, Elizabeth B. De Sousa Fernandes Perna, Julian Mateus, Kim P. C. Kuypers, Eef L. Theunissen, Francina Fonseca, Marta Torrens, Jan RamaekersAbstract:Mephedrone (4-MMC, Mephedrone) is a synthetic cathinone derivative included in the class of New Psychoactive Substances. It is commonly used simultaneously with alcohol (ethanol). The aim of the present study was to evaluate the interactions on subjective, cardiovascular and hormone effects and pharmacokinetics between Mephedrone and alcohol in humans. Eleven male volunteers participated as outpatients in four experimental sessions in a double-blind, randomized, cross-over, and placebo-controlled clinical trial. Participants received a single oral dose of 200 mg of Mephedrone plus 0.8 g/kg of alcohol (combination condition); 200 mg of Mephedrone plus placebo alcohol (Mephedrone condition); placebo Mephedrone plus 0.8 g/kg of ethanol (alcohol condition); and placebo Mephedrone plus placebo alcohol (placebo condition). Outcome variables included physiological (blood pressure, heart rate, temperature, and pupil diameter), psychomotor (Maddox wing), subjective (visual analogue scales-VAS, ARCI-49 item short form, and VESSPA questionnaire), and pharmacokinetic parameters (Mephedrone and ethanol concentrations). The study was registered in ClinicalTrials.gov, number NCT02294266. The Mephedrone and alcohol combination produced an increase in the cardiovascular effects of Mephedrone and induced a more intense feeling of euphoria and well-being in comparison to the two drugs alone. Mephedrone reduced the sedative effects produced by alcohol. These results are similar to those obtained when other psychostimulants such as amphetamines and MDMA are combined simultaneously with alcohol. The abuse liability of Mephedrone combined with alcohol is greater than that induced by Mephedrone alone.
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dose response pharmacological study of Mephedrone and its metabolites pharmacokinetics serotoninergic effects and impact of cyp2d6 genetic variation
Clinical Pharmacology & Therapeutics, 2019Co-Authors: Eulàlia Olesti, Magí Farré, Esther Papaseit, Mitona Pujadas, Marta Torrens, Marcel Li Carbo, Clara Perezmana, Samanta Yuberolahoz, Óscar J. PozoAbstract:Mephedrone (MEPH), the most widely consumed synthetic cathinone, has been associated with acute toxicity episodes. The aim of this report was to study its metabolic disposition and the impact of genetic variation of CYP2D6 on MEPH metabolism, in a dose range compatible with its recreational use. A randomized, crossover, phase I clinical trial was performed. Subjects received 50 and 100 mg (n = 3) and 150 and 200 mg (n = 6) of Mephedrone and were genetically and phenotypically characterized for the CYP2D6 allelic variation. Our results showed a linear kinetics of Mephedrone at the dose range assayed: plasma concentrations, cardiovascular and subjective effects, and blood serotonin concentrations all correlated in a dose-dependent manner. Mephedrone metabolic disposition is mediated by CYP2D6. Mephedrone pharmacology presented a linear dose-dependence within the range of doses tested. The metabolism of Mephedrone by CYP2D6 implies that recreational users with no or low CYP2D6 functionality are exposed to unwanted acute toxicity episodes.
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Mephedrone Concentrations in Cases of Clinical Intoxication.
Current pharmaceutical design, 2018Co-Authors: Esther Papaseit, Eulàlia Olesti, Rafael De La Torre, Marta Torrens, Magí FarréAbstract:Background Mephedrone (4-methylmethcathinone, 4-MMC), a ring-substituted synthetic cathinone derivative has become established as a permanent illicit drug in the dynamic new psychoactive substances (NPS) scene. Objective This review summarizes current knowledge on Mephedrone concentrations in biological samples from cases of acute intoxications (fatal and non-fatal), pharmacokinetics studies, wastewater and anonymous pooled urine analysis in order to provide an overview of the reliable scientific knowledge on toxicokinetics of Mephedrone in humans. Method The PubMed® database complemented with Google Scholar® was systematically searched to find published cases of Mephedrone intoxications. The searches were done using the keyword "Mephedrone OR 4- methylmethcathinone" in association to each of the following strategies: i) "intoxication OR poisoning"; ii) "(blood OR serum OR plasma") OR "urine" OR ("saliva OR oral fluid") OR "hair"; iii) "forensic toxicology samples"; iv) "wastewater OR sewage OR pooled urine" and v) "toxicity OR death OR fatal". Results Since 2010, a total of 97 fatal cases and 57 non-fatal intoxication cases were identified that presented Mephedrone concentrations in human biological matrices attributed directly or indirectly to Mephedrone. Typical subjects involved were young male with concomitant use of other drugs (psychostimulants, cannabis, alcohol and other depressants). Mephedrone mean blood concentration from fatal cases was 2,663 ng/mL (range 51-22,000 ng/mL), from non-fatal cases was 166 ng/mL (range, 13-412 ng/mL), that resulted in a similar range from data found in controlled studies with no acute toxicity associated (135 ng/mL, range 52-218 ng/mL). Forensic epidemiology studies based on wastewater and anonymous pooled urine analysis point towards similar variations in use (nightclub scene) to those self-reported in surveys and questioners. Conclusion Mephedrone blood concentrations in cases of fatal intoxications were higher than in non-fatal cases. In both cases, great variability in Mephedrone concentration potentially attributable to interindividual differences in pharmacokinetics-pharmacodynamics and poly-drug use complicates the interpretation of the forensic toxicological analysis.
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Pharmacokinetics of Mephedrone and Its Metabolites in Human by LC-MS/MS
The AAPS Journal, 2017Co-Authors: Eulàlia Olesti, Magí Farré, Esther Papaseit, Aristotelis Krotonoulas, Mitona Pujadas, Rafael De La Torre, Óscar J. PozoAbstract:Mephedrone is a synthetic cathinone consumed as a recreational drug. Recently, it was identified several of its metabolites in vivo in humans but there is little information about its pharmacokinetics in plasma and urine. Although several analytical methods have been proposed for Mephedrone quantification in different matrices, none are available for its metabolites. Therefore, the aim of the study was to develop and validate an analytical method using liquid chromatography-tandem mass spectrometry for the quantification of Mephedrone, nor-Mephedrone, N -succinyl-nor-Mephedrone, 1′-dihydro-Mephedrone, and 4′-carboxy-Mephedrone. The method was validated in human plasma and urine and in rat brain homogenates. Six healthy male subjects, recreational users of new psychoactive substances, ingested 150 mg of Mephedrone within the context of a clinical trial. 4′-Carboxy-Mephedrone, followed by nor-Mephedrone, was the most abundant metabolites found in plasma. Dihydro-Mephedrone represented 10% of the amount of Mephedrone in plasma and N -succinyl-nor-Mephedrone was the metabolite eliminated with the longer half-life of 8.2 h. In urine, 4′-carboxy-Mephedrone was the main metabolite excreted with amounts recovered being about 10 times those of Mephedrone. Additionally, the validated method was used to test metabolite ability to cross the blood-brain barrier in vivo in rats with Mephedrone and nor-Mephedrone as the main active compounds present in the brain. The method described is useful for the determinations of Mephedrone and metabolites in biological samples. Graphical Abstract ᅟ