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Simon H. Cosbey, K. Mephedrone 4-methylmethcathinone is the beta-keto analogue of 4-methylmethylamphetamine. Before its control in April , it became popular as a legal high in the United Kingdom, displacing methylenedioxymethylamphetamine as the stimulant drug of choice. The drug has stimulant and psychoactive properties, and therefore has forensic significance in criminal and morbid toxicology. The purpose of this study was to survey casework involving the drug impaired driving and sudden death. The cases were received in the laboratory for analysis between late and the end of Analysis of blood samples for mephedrone was conducted by liquid chromatography—mass spectrometry LC—MS. Routine screening for alcohol and a range of other pharmaceuticals and drugs of abuse was conducted using a combination of enzyme-linked immunoassay, gas chromatography GC headspace, GC—MS and high-performance liquid chromatography with diode array detection. Mephedrone was detected in a total of 12 fatal cases. Most of these cases involved death by mechanical means; in two cases, death was attributed directly to mephedrone intoxication blood concentrations of 2. Mephedrone was detected in a total of 32 impaired driving cases. Blood concentrations ranged up to 0. The casework evidence in this study indicated that recreational use of the drug can produce to blood levels as high as 0. In the United Kingdom, the legislation used to control drugs of abuse is the Misuse of Drugs Act The listing of controlled substances in the legislation is extensive, but until the s, most of the drugs seized under this legislation were predictable and largely limited to cannabis, heroin, amphetamine and cocaine. Following the publication of the book Phenethylamines I have Known and Loved in 1 , there was an increase in the availability of synthetic psychoactive phenethylamine drugs. These drugs were related to amphetamine, but chemical alteration of the molecular structure changed the nature of the psychoactive effects and the status of legal control. Ring-substituted phenethylamine drugs such as methylenedioxymethylamphetamine MDMA were widely abused in the s and s and are commonly encountered in most forensic science laboratories. Generic legislation was enacted in many jurisdictions to control such drugs, and eventually served to cover virtually all possible analogues. These were eventually classified as Class C drugs under the Misuse of Drugs Act , effective from December 23, At approximately the same time, another group of drugs was appearing on the illicit drug scene; these cathinones are also structurally related to amphetamine. Cathinone itself 2-aminophenyl propanone is one of a number of alkaloids found in fresh leaves of Catha Edulis Khat , a stimulant drug usually associated with North Africa. This compound is actually the beta-keto analogue of amphetamine. The cathinone drug most frequently encountered in the drugs laboratory is mephedrone. Although the markings on the packages indicated that the powder should not be used for human consumption, it was widely accepted that the alleged bath salts or plant food were being used for their psychoactive activity. In early , there were many local press reports surrounding the drug, which was implicated in the deaths of many young people 3 , 4. The Forensic Science Northern Ireland Toxicology laboratory also conducts analytical work on drug seizures on behalf of law enforcement agencies. In the months prior to the control of cathinone derivatives, mephedrone seizures predominated. By March , mephedrone accounted for over half of all powder and tablet seizures submitted to the laboratory. As a consequence, the analytical toxicology strategy used to process both criminal and coroner toxicology casework was reviewed. Routine toxicological screening was considered to be largely unsuitable for mephedrone detection, particularly at low or even recreational levels. It was decided to screen appropriate samples by liquid chromatography—mass spectrometry LC—MS specifically for mephedrone, in addition to routine toxicology screening. The history and circumstances of submitted cases were assessed to determine whether mephedrone analysis could be useful. Toxicology casework analyzed at the laboratory includes the following case types: i coroner cases, which include samples submitted by the State Pathologist for routine and specific toxicology analysis. Casework includes road traffic victims, sudden deaths, suicides and those postmortem cases in which there is a suspicion that a crime may have occurred e. Cases of this type include rape, assault and driving under the influence of drugs. Most casework involves the analysis of blood samples clinical and postmortem , although urine and gastric contents are also occasionally analyzed. All of the casework samples considered in this study were whole blood, preserved with sodium fluoride and potassium oxalate. All impaired driving samples were refrigerated on submission to the laboratory with a likely pre-submission history of refrigeration storage instructions issued to police. All coroner cases were frozen upon submission and refrigerated during the period in which laboratory work was undertaken. Routine screening was conducted on the vast majority of casework in self-contained analytical batches incorporating calibrators and quality controls QCs independent spiked samples validating the calibration and will not be discussed in detail here. Some details of this analytical approach have been previously described 5. Although LC—MS analysis for mephedrone was not conducted in all cases received at the laboratory, it was requested in those cases in which there was a reasonable risk of its involvement. In particular, those cases involving the sudden death of young persons and mechanical suicide were targeted. For crime casework primarily impaired driving cases , mephedrone was targeted if the history or observed symptoms suggested that it may be present. Analysis for mephedrone began in late and the results of this study included casework received until the end of Approximately cases were analyzed in this period; of these cases, approximately would have been screened for mephedrone. Eluent B was deionized water Elga purification system and formic acid analytical grade; Fisher Scientific 1 mL of acid added per liter of water. The eluents were run on a binary gradient of A:B, starting at and increasing to during a min analysis. Prazepam purchased from Sigma, UK was used to prepare a 0. An internal standard solution of 0. For mephedrone Toronto Research Chemicals , a 0. Individual working solutions were prepared in methanol at concentrations of 0. Liquid—liquid extraction was used to isolate the analytes for instrumental analysis. This mixture was then vortexed for 1 min and centrifuged for 10 min at 4, rpm. Sheep blood was used to prepare blank and control samples calibrators and QCs. Identification of an analyte was established using both retention times and spectral matches against instrument libraries. Mephedrone eluted with a retention time of approximately 2. A set of calibrators prepared in blood was analyzed within each batch. A coefficient of determination r 2 of greater than 0. The reproducibility of the method was shown by analyzing both the CV of relative retention time and the spectral match between batches over time. No matrix effects were found. Samples of postmortem femoral blood sometimes with urine and gastric contents were submitted by the State Pathology Department. These were analyzed for mephedrone, where applicable, in addition to routine toxicology screening. Analysis was repeated after dilution when analyte concentrations were outside the upper calibration range of the assay. The results of the casework found to contain mephedrone have been compiled, along with additional information such as case history and circumstances, estimated interval before death and postmortem findings. Samples of blood occasionally urine were submitted by the police service. The results of the casework found to contain mephedrone have been compiled, along with additional information such as case history and circumstances and estimated interval before sample collection. Screening of appropriate casework for mephedrone began in late and the results of positive casework are outlined in the following. The cases have been divided by case type. Sudden death cases are those in which the pathologist wishes to eliminate the presence of drugs and has requested toxicological examination. Consequently, a blood sample was taken for analysis. Analysis for mephedrone took place if its presence was suspected either by police observation, case history or suspect admission or if the suspect's age was below 30 years. The results of the sudden death cases in which mephedrone was found, including additional information such as case history and disposition, are outlined in Table I. Results of Sudden Death cases in which mephedrone was found along with case history and disposition. The results of the impaired driving cases in which mephedrone was found as the only drug are outlined in Table II. The time lapse refers to the time between the incident and the collection of the blood sample. Observed symptoms do not necessarily relate to the detected level of mephedrone due to delays in taking the sample. Results of the impaired driving cases in which mephedrone was found as the only drug. Time lapse refers to the time between the incident and the blood sample being taken. All samples were whole blood. The results of the impaired driving cases in which mephedrone was found as the only drug are outlined in Table III. Observed symptoms do not necessarily relate to the detected drug levels due to delays in taking the sample. The abuse of mephedrone as a legal psychoactive alternative has received significant media attention throughout the United Kingdom, primarily during and the first half of In Northern Ireland, mephedrone also became newsworthy and the drug was anecdotally linked to depression and suicide 4. The government generically controlled the drug from April 16, Although the available information on these drugs was scant, it was considered that their toxicity was similar to other amphetamine-like compounds, and therefore, they were controlled as Class B compounds under the Misuse of Drugs Act Although toxicology data on mephedrone and other cathinones are limited, many case reports have been published to date. The first report of confirmed toxicity associated with recreational mephedrone use was presented in September of at the North American Congress of Clinical Toxicology, San Antonio, Texas 6. A year-old male initially ingested mg of mephedrone and followed this shortly afterwards with the intramuscular injection of 3. Initial symptoms were palpitations, blurred tunnel vision, chest pressure and sweating. These symptoms settled over the next 4 h after oral lorazepam and he was discharged after 6 h. The estimated serum mephedrone concentration was 0. No other drugs or alcohol were detected. James et al. The most common clinical features reported were typical for a sympathomimetic agent, including tachycardia, palpitations, agitation, anxiety, sweating, mydriasis, tremor and hypertension. Although there are limitations with these data, it seems likely that mephedrone toxicity appears largely similar to that of amphetamine. In a recent case report by Dickson et al. The mephedrone concentration in the blood was found to be 0. The cause of death was attributed to mixed drug toxicity; it would be difficult to speculate the degree of mephedrone involvement. In another paper by Wikstrom et al. In the first case, hair analysis demonstrated chronic methedrone intake and the blood methedrone concentration was 9. His postmortem blood concentration was 8. No other drugs or alcohol were detected in either case. In a recent paper by Maskel et al. In one of the cases, death was attributed to the adverse effects of mephedrone, with contributing factors of coronary artery disease and myocardial fibrosis. In the second case, mephedrone was considered to be the primary cause of death blood mephedrone level of 2. Apparently, the toxicity of mephedrone has broadly similar characteristics to other amphetamine-like compounds, related to their general sympathomimetic effects. These toxic effects, therefore, include tachycardia, hypertension, hyperthermia, convulsions and cardiac failure. Although high blood amphetamine concentrations have been recorded in individuals surviving high amphetamine levels particularly in tolerant addicts , fatality is not uncommon. In a study of 17 deaths attributed solely to amphetamine, femoral blood concentrations ranged from 1. A total of 12 mephedrone-related fatalities are reported here. Of these deaths, most were due to mixed drug toxicity, mechanical suicide and road traffic collisions; only two were attributed directly to mephedrone toxicity. In both of these cases, the case histories were strongly indicative of drug abuse during the hours preceding death. In Case 2, the time interval between ingestion and death is likely to have been relatively short within several hours and no other drugs were found, except for a low concentration of alcohol. The measured mephedrone concentration was 2. In Case 6, antemortem samples were analyzed, the earliest of which had a mephedrone concentration of 1. Although in this case, the time interval between ingestion and the first antemortem sample is not known precisely, it is likely to have been at least a few hours. The presence of a low level of TFMPP in this case is likely to have had some exacerbating effect on stimulant-like toxicity. In Case 6, many antemortem samples were taken over a period of 3. This estimation of 3—4 h appears to be a little shorter than the published elimination half-lives of other amphetamine-like drugs If the elimination characteristics of mephedrone are as short as they appear to be, then the measured mephedrone levels at the time of ingestion could have been significantly higher in many of the studied cases. In those fatal cases involving mephedrone but in which death was not directly attributed directly to the drug, mephedrone concentrations ranged from 0. It is useful to consider impaired driving cases because drug levels in these cases have been associated with observed impairment and results have not been complicated by possible postmortem redistribution effects. Of these, mephedrone was the only drug detected in nine cases. Therefore, reported effects are likely to have arisen only as a result of mephedrone toxicity. In an additional 23 cases, mephedrone was found to be present along with one or more other drugs. Consequently, mephedrone is unlikely to have been the sole impairing drug. The highest mephedrone concentrations reported in these cases were 0. The blood concentrations found in the nine cases reported time interval up to 3 h ranged from 0. In a subset of these results cases associated with a time interval of less than 1. Of the 23 cases in this category, the cases with the highest mephedrone concentrations are outlined in Table IV. Results of 3 impaired driving cases with high mephedrone concentrations and other drugs present. In the seven cases in which the time interval was less than 1. The data from all impaired driving cases are tabulated in Table V. Results of all impaired driving cases. Comparison of mephedrone-only cases and mephedrone present with at least 1 other impairing drug. Data for fatal cases where death was not directly attributed to mephedrone is also given. The negative bias associated with the median values indicates that the overall composition of the data sets is biased toward lower values. This study presents mephedrone concentrations in both fatal and impaired driving casework. Subjects were predominantly young adult males. This concentration is similar to the single case reported by Maskell 10 , in which mephedrone was considered to be the primary cause of death blood mephedrone concentration of 2. The evidence presented in this study indicates that recreational use of mephedrone can produce to blood concentrations at least as high as 0. On the basis of the data presented, fatality due to mephedrone alone is likely to be associated with blood mephedrone concentrations of greater than 2. The limited data available in this study suggest that the elimination half-life of mephedrone is relatively short, a fact of some significance in the interpretation of quantitative results. Google Scholar. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Skip Nav Destination Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Methods and Materials. Sudden Death Case Samples. Impaired Driving Case Samples. Impaired driving case results. Article Navigation. Cosbey , Simon H. Email: Simon. Oxford Academic. Laota Peters. Amy Quinn. Alastair Bentley. Cite Cite Simon H. Select Format Select format. Permissions Icon Permissions. Abstract Mephedrone 4-methylmethcathinone is the beta-keto analogue of 4-methylmethylamphetamine. Table I. Interval between Ingestion and Death. Toxicology Findings. Case Disposition. Case 1 eceased was a 17—year-old male. After getting into difficulty in the early hours, an ambulance was called, but he had no pulse upon arrival at hospital and was declared dead a short time later. There was no evidence or pre-existing natural disease or trauma. Case 2 Deceased was a 20—year-old male who collapsed at a party. Suspicions were that he had taken drugs. There was no evidence of pre-existing natural disease or trauma. Case 3 Deceased was a 23—year-old male. Suicidal hanging. Unknown Blood Mephedrone 0. There were no other findings of note at autopsy. Case 4 Deceased was a 24—year-old male who was an occupant in a vehicle involved in a road traffic collision. He was taken to hospital but died of his injuries 28 hours later. An ante-mortem sample was also collected approximately 1 hour after the incident. Unknown Ante-mortem Blood Mephedrone 0. Prior to autopsy organ harvest had been performed. Case 5 Deceased was a 20—year-old male who was found dead in bed. He was thought to have been drinking or taking drugs recently. Case 6 Deceased was a 21—year-old male who was hospitalized after becoming ill following suspected drug use. He died in Intensive Care. A number of ante-mortem samples were obtained, each of which consisted of whole blood. The cause of death was given as' Mephedrone Toxicity'. Case 7 History : Deceased was a 17 year-old male with a history of drug abuse. He was thought to be abusing cannabis, mephedrone and diazepam. There was no evidence of natural disease. Case 8 Deceased was a 17 year-old male with a history of drug abuse. Suicidal hanging, after an argument with his partner. Case 9 Deceased was a 17 year-old male; suicidal hanging. There were in excess of one hundred fine superficial scratch abrasions on the outer aspect of the left upper arm and forearm. These were consistent with self-infliction and indicative of low self-esteem. Case 10 Deceased was a 34 year-old male. He was reported as acting strangely recently and was known to abuse drugs including ketamine and alcohol. His body was recovered from a river. The lungs were expanded, had a doughy consistency and abundant fluid could be expressed from their cut surfaces. Case 11 Deceased was a 17 year-old male with a history of psychiatric problems. Found dead in the bathroom Unknown Blood Mephedrone 0. The lungs were expanded, over-riding the mediastinum and copious fluid could be expressed from the cut surfaces. Case 12 Deceased was a 17 year-old female with a history of depression for which she was prescribed fluoxetine. Took her own life by hanging. Open in new tab. Table II. Observed Symptoms. Time Lapse Hours. In the space of 1 month this individual was stopped and arrested by police twice due to the nature of his driving. Cannabis resin was also seized from the subject on his second arrest. Subject was agitated, hyperactive, twitchy, unable to make eye contact and failed a FIT impairment test. A bag of white powder, later confirmed to be mephedrone, was seized from the subject. Subject appeared agitated and hyperactive. He had wide, bloodshot eyes and was sweating and chewing the inside of his cheeks. Subject had glazed eyes and slurred speech. He undertook a FIT test which he failed. Subject had glazed eyes. Subject was searched and a bag of white powder was seized. The powder was claimed by the subject as mephedrone. Police believed subject to be under the influence of drugs. Subject had dilated pupils and was unsteady on his feet. A package with white powder was found in the car. Herbal cannabis was also seized from the subjects address. Subject had slurred speech and glazed eyes. Other drug paraphernalia was found in the vehicle. Subject was uncoordinated and had slurred speech. Subject also failed a preliminary impairment test. A bag containing white powder was also found in the subject's sock. This was later identified as 0. His eyes were glazed and rolling in his head and he appeared dazed and confused with slurred speech. Table III. Subject and Story. Time lapse Hours. Powder was observed around subject's nostrils, foam around the mouth, eyes constricted. Subject was drowsy and at times his speech was incoherent. The subject was found at the hospital. The subject was nervous and agitated; his eyes were glazed and bloodshot. He was distracted with slurred speech and a dry month. Police observed white powder under the subject's nose. He was agitated with dilated pupils and slurred speech. The subject's eyes were glazed and his behaviour was erratic. The subject had diluted pupils, glazed eyes and slurred speech. He appeared unsteady on his feet. Subjects behaviour was erratic, he had glazed eyes and slurred speech. The subject admitted to drinking alcohol and taking prescribed diazepam. The subject had slurred speech and smelt of intoxicating liquor. Several bags containing white powder and bags also containing herbal cannabis were seized from the suspect at his home address. The powder was confirmed to be mephedrone. Subject appeared confused and jerky with slurred speech, his pupils appeared unusually large. During a search of the vehicle, 27 capsules containing yellow powder and a small bag of yellow powder were seized. The subject's pupils were pin -point and he had yellow powder on his tongue. Police were called to a hit and run collision where the injured party believed the driver of the other vehicle to be intoxicated. A bag of white powder seized from the scene was confirmed to be mephedrone. The subject appeared drunk and had white powder around his nostrils. He was chewing on his jaw and grinding his teeth. The subject had difficulty standing unaided. His speech was slurred and his eyes were bloodshot and appeared heavy. The subject failed a FIT test. Herbal cannabis and a bag containing white powder were seized from the subject. The subjects complexion was flushed, pupils dilated and speech incoherent. White powder was observed around his nostrils. During search large quantities of both herbal cannabis and white powder were seized from the subject and his vehicle. Odour of chemical substances inside the car. A bag of white powder was also found and they were all confirmed to be mephedrone. Subject appeared nervous and agitated, unable to maintain eye contact. Subject had slurred speech was unsteady on his feet and had white powder under both nostrils. Subject was later brought to police station by his father. Subject had glazed eyes, his speech was incoherent and he appeared irrational. The subject's driving was described as dangerous during the pursuit. Subject was detained as he ran from the vehicle and admitted being high on mephedrone whilst driving. Subject was observed exiting the driver's seat and had 3 passengers in the car. All passengers were detained and admitted to consuming alcohol. All denied driving. A bag containing several blue tablets was found in his possession. Subject was swaying and unsteady on his feet. Seen on CCTV parking vehicle. Subject admitted to taking 2 diazepam tablets before leaving home. Subject appeared highly intoxicated, he was unsteady on his feet and had trouble standing unaided. Subject was unsteady, had glazed eyes and slurred speech. Table IV. Time interval Hrs. Table V. Impaired Driving Mephedrone only 0. Forensic chemistry of substance misuse: A guide to drug control, Chapter 6. Recreational use of mephedrone 4-methylmethcathinone, 4-MMC with associated sympathomimetic toxicity. Google Scholar Crossref. Search ADS. Multiple drug toxicity caused by the co-administration of 4-methylmethcatinone mephedrone and heroin. Two fatal intoxications with the new designer drug methedrone 4-methoxymethcathinone. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals. Issue Section:. Download all slides. View Metrics. Email alerts Article activity alert. Advance article alerts. New issue alert. Receive exclusive offers and updates from Oxford Academic. Related articles in Web of Science Google Scholar. Citing articles via Web of Science Blood Mephedrone 0. Other than pulmonary oedema, autopsy and histological examination of tissue sections showed nothing of note. Blood Mephedrone 2. There was evidence of aspiration, however this was believed to be a terminal event. The findings at autopsy were consistent with hanging. Ante-mortem Blood Mephedrone 0. Death was due to a severe head injury. Apart from pulmonary oedema, there was nothing of note at autopsy or on histological examination of tissue sections. Apart from small amounts of blood-stained fluid in the stomach and abdomen, there were no findings of note at autopsy or on histological examination of tissue sections. The findings were consistent with hanging. The trachea and main bronchi contained slightly blood-stained fluid. Found dead in the bathroom. There was frothy pale fluid within the trachea. Case 12 22 yr old male stopped by police at a vehicle check-point. Case 15 19 yr old male arrested as a result of a 2-car collision. Case 16 21 yr old male stopped by police for erratic driving. Case 17 a young female was arrested after police were tasked to a single vehicle collision causing damage to private property. Case 19 19 yr old male stopped at a vehicle check-point. Case 21 22 yr old male stopped by police after they observed him crash into a petrol pump. Case 22 20 yr old male stopped by police due to erratic driving and weaving across lanes. Case 32 21 yr old male arrested for a damage only hit and run.

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