Mephedrone - Oxford Journals - Oxford University Press

Journal of Analytical Toxicology 2013;37:74 –82 doi:10.1093/jat/bks094

Article

Mephedrone (Methylmethcathinone) in Toxicology Casework: A Northern Ireland Perspective Simon H. Cosbey1*, K. Laota Peters1, Amy Quinn1 and Alastair Bentley2 1 Forensic Science Northern Ireland, 151 Belfast Rd., Carrickfergus, BT38 8PL, and 2Northern Ireland State Pathologist’s Department, Institute of Forensic Medicine, Grosvenor Rd., Belfast BT12 6BS

*Author to whom correspondence should be addressed. Email: [email protected]

Mephedrone (4-methylmethcathinone) is the beta-keto analogue of 4-methylmethylamphetamine. Before its control in April 2010, 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 2009 and the end of 2010. 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 enzymelinked 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 2.1 and 1.94 mg/L). Mephedrone was detected in a total of 32 impaired driving cases. Blood concentrations ranged up to 0.74 mg/L (mean 0.21, median 0.10). The casework evidence in this study indicated that recreational use of the drug can produce to blood levels as high as 0.74 mg/L, although the most common value encountered is likely to lie between 0.2 and 0.3 mg/L.

Introduction In the United Kingdom, the legislation used to control drugs of abuse is the Misuse of Drugs Act (1971). The listing of controlled substances in the legislation is extensive, but until the 1990s, 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 1991 (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 1990s and 2000s 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. In 2007, the Ecstasy drugs (such as MDMA) were largely replaced by piperazine derivatives such as benzylpiperazine

(BZP). These were eventually classified as Class C drugs under the Misuse of Drugs Act (1971), effective from December 23, 2009. 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-amino-1-phenyl 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. It is a white powder known by names such as M-Cat, Meow-Meow and Bubbles, and has been sold on the Internet as “plant food” or “bath salts.” Before the drug was controlled, packages containing the drug were sold to members of the public in various retail outlets, head shops and on the Internet. 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 2010, 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 2010, 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. This paper reports on those cases in which mephedrone was detected, and outlines case histories, other drugs/alcohol present, cause of death and pathology information (if applicable).

Methods and Materials 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.g., murder or

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suspicious death); (ii) criminal toxicology cases, which include samples submitted by the police from living persons. 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. Briefly, the analysis consisted of three elements: (i) enzyme-linked immunoassay (ELISA), i.e., screening for a standard panel of common drugs (amphetamine, methylamphetamine, opiates, barbiturates, cocaine, cannabis and benzodiazepines); (ii) gas chromatography (GC)–MS basic drug screen for a wide range of basic and neutral drugs including antidepressants and tranquillizers; (iii) high-performance liquid chromatography (HPLC) screening with diode array detection, an analysis complementing the GC–MS basic drug screen. Some details of this analytical approach have been previously described (5). Targeted analysis Targeted GC –MS, HPLC and LC –MS were conducted where necessary, depending upon the case circumstances and results of the screening tests. 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 2009 and the results of this study included casework received until the end of 2010. Approximately 800 cases were analyzed in this period; of these cases, approximately 300 would have been screened for mephedrone. LC –MS Reagents and standards The mobile phase for HPLC was based on the binary mixing of eluents A and B. Eluent A was HPLC grade methanol (Fisher Scientific, Palo Alto, CA) and formic acid (analytical grade; Fisher Scientific) (1 mL of acid added per liter of methanol). 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 50:50 and increasing to 90:10 during a 20-min analysis. Prazepam ( purchased from Sigma, UK) was used to prepare a 0.1% stock solution in methanol. An internal standard solution of 0.001% prazepam was prepared in M-Tris (Fisher Scientific, UK). For mephedrone (Toronto Research Chemicals), a 0.1% stock solution was prepared in methanol. Individual working solutions were prepared in methanol at concentrations of 0.001, 0.0001 and 0.00001% by dilution. Extraction method Liquid–liquid extraction was used to isolate the analytes for instrumental analysis. One milliliter of t-butylmethylether (TBME, HPLC grade) was added to 0.5 mL of internal standard solution, followed by 0.5 mL of a body fluid sample in a screw-capped culture tube. This mixture was then vortexed for 1 min and centrifuged for 10 min at 4,500 rpm. The upper organic layer was removed to an autosampler vial, evaporated to dryness under nitrogen at room temperature, reconstituted in 25 mL of methanol and analyzed by LC–MS. Sheep blood was used to prepare blank and control samples (calibrators and QCs). Instrumentation LC–MS analysis was conducted using an Agilent LCMSD XCT ion-trap mass spectrometer with electrospray interface technology. The software used for data acquisition was Chemstation for LC3D and LC/MSD Trap Software 4.2SR1. An Agilent Zorbax SB-C18 column was used (2.1 150 mm, 3.5 mm) operating at a flow rate of 0.25 mL/min. The column temperature was maintained at 408C. Positive ionization was performed, scanning a range of 50– 550 m/z using the following parameters: nebuliser nitrogen at 40 psi, dry gas at 10 L/min and dry temperature 3258C. Identification of an analyte was established using both retention times and spectral matches against instrument libraries. The following LC –tandem mass spectrometry (MS-MS) parameters were used: analyte, mephedrone; parent ion, m/z 177.6; daughter ion, m/z 159.6; amplitude, 1.4; fragmentation cutoff, 100. Mephedrone eluted with a retention time of approximately 2.5 min. Method calibration A set of calibrators prepared in blood was analyzed within each batch. The calibrators were used to generate calibration curves at 20, 50, 100, 200, 500, 1,000 and 2,000 mg/L. A coefficient of determination (r 2) of greater than 0.98 was achieved. Prepared QC sample extracts (quantitation agreeing within +20%) were used to validate quantitation within each batch. The limit of quantification (LOQ) for mephedrone was 20 mg/L (lowest calibrator) and the limit of detection (LOD) for the assay (with satisfactory spectral match) was considered to be 1 mg/L in blood and 2 mg/L in urine. The precision of the method was determined by analyzing the coefficients of variation (CVs) of both relative and absolute retention time and spectral matches within a batch (n ¼ 3) of 0.0001% working standards. The reproducibility of the method was shown by analyzing both the CV of relative retention time and the

Mephedrone (Methylmethcathinone) in Toxicology Casework: A Northern Ireland Perspective 75

spectral match between batches over time. No matrix effects were found. Sudden Death Case Samples 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. Impaired Driving Case Samples Samples of blood (occasionally urine) were submitted by the police service. 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 and estimated interval before sample collection. Results Screening of appropriate casework for mephedrone began in late 2009 and the results of positive casework are outlined in the following. Approximately 300 cases were analyzed for the presence of mephedrone over this period; in approximately 15% of those cases, mephedrone was detected. 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. Impaired driving cases are those in which the police have had suspicion that the subject’s driving was impaired by alcohol and/or drugs. 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. Sudden death cases 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. Impaired driving case results Impaired driving cases: Only mephedrone detected 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. 76 Cosbey et al.

Impaired driving cases: Mephedrone detected with other drugs/alcohol The results of the impaired driving cases in which mephedrone was found as the only drug are outlined in Table III. 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 drug levels due to delays in taking the sample. Discussion The abuse of mephedrone as a legal psychoactive alternative has received significant media attention throughout the United Kingdom, primarily during 2009 and the first half of 2010. 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, 2010. 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 (1971). 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 2009 at the North American Congress of Clinical Toxicology, San Antonio, Texas (6). A 22-year-old male initially ingested 200 mg of mephedrone and followed this shortly afterwards with the intramuscular injection of 3.8 g of mephedrone dissolved in water. Initial symptoms were palpitations, blurred tunnel vision, chest pressure and sweating. Continuing features of sympathomimetic toxicity continued with heart rate of 105, blood pressure of 177/111 and dilated pupils of 7 mm. These symptoms settled over the next 4 h after oral lorazepam and he was discharged after 6 h. The estimated serum mephedrone concentration was 0.15 mg/mL. No other drugs or alcohol were detected. James et al. (7) outlined the epidemiology and clinical effects of these compounds, as reported to the National Poisons Information Service by the healthcare professionals involved in their care. 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. (8), the accidental death of a 22-year-old male was described. The mephedrone concentration in the blood was found to be 0.5 mg/L and morphine concentration was 0.06 mg/L. 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. (9), 2 fatal intoxications with 4-methoxymethcathinone (methedrone, beta-keto-pmethoxymethylamphetamine) were reported. In the first case, hair analysis demonstrated chronic methedrone intake and the blood methedrone concentration was 9.6 mg/L. In the second case, a 23-year-old man was admitted to hospital with

Table I. Results of Sudden Death cases in which mephedrone was found along with case history and disposition History

Interval between Ingestion and Death

Toxicology Findings

Case 1 eceased was a 17 –year-old male. Witnesses reported that he was ‘snorting mephedrone’ most of the weekend and had recently ingested some powdered mephedrone. 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.

Short (, 3hrs)

Blood Mephedrone 0.22 mg/L

Case 2 Deceased was a 20– year-old male who collapsed at a party. Suspicions were that he had taken drugs.

Short , 3hrs


Case 3 Deceased was a 23– year-old male. Suicidal hanging.

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.

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.

Unknown

Unknown

Other Drugs Alcohol - none detected BZP (benzylpiperazine) 1.83 mg/L TFMPP (trifluoromethylphenylpiperazine) 0.14 mg/L Dextromethorphan 0.96 mg/L 11-nor-delta-9-tetrahydrocannabinolic acid 0.13 mg/L Blood Mephedrone 2.10 mg/L Other Drugs Alcohol † Blood 19 mg/dL † Urine 49 mg/dL Blood Mephedrone 0.11 mg/L Other Drugs Alcohol † Blood 37 mg/dL, † Urine 56 mg/dL Diazepam 0.39 mg/L Ante-mortem Blood Mephedrone 0.06 mg/L

Case Disposition

Other than pulmonary oedema, autopsy and histological examination of tissue sections showed nothing of note. There was no evidence or pre-existing natural disease or trauma. The cause of death was given as ‘Mixed Drug Toxicity’.

There was evidence of aspiration, however this was believed to be a terminal event. There was no evidence of pre-existing natural disease or trauma. The cause of death was given as ‘Poisoning by Mephedrone’.

The findings at autopsy were consistent with hanging. There were no other findings of note at autopsy.

Death was due to a severe head injury. Prior to autopsy organ harvest had been performed.

Other Drugs Alcohol † Blood 11 mg/dL Diazepam 0.20 mg/L 11-nor-delta-9-tetrahydrocannabinolic acid Post-mortem Blood Mephedrone 0.005 mg/L (approximately (,LOQ))

Unknown

Other Drugs Alcohol none detected Diazepam 11-nor-delta-9-tetrahydrocannabinolic acid Blood Mephedrone 0.04 mg/L Other Drugs Alcohol none detected MDMA 0.51 mg/L Diazepam 1.13 mg/L Codeine 0.04 mg/L 11-nor-delta-9-tetrahydrocannabinolic acid

Apart from pulmonary oedema, there was nothing of note at autopsy or on histological examination of tissue sections. The cause of death was given as ‘Poisoning by MDMA and Mephedrone’.

(continued)

78 Cosbey et al.

Table I. Continued History

Interval between Ingestion and Death

Toxicology Findings

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.

Unknown

Ante-mortem: Blood Mephedrone † Sample 1 (06:00 † Sample 2 (08:00 † Sample 3 (09:00 † Sample 4 (09:30

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. Suicidal hanging.

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.

Unknown

Unknown

Unknown

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.

Unknown

Case 11 Deceased was a 17 year-old male with a history of psychiatric problems. Found dead in the bathroom

Unknown

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.

Unknown

Case Disposition

hrs)1.94 mg/L hrs)1.69 mg/L hrs)0.94 mg/L hrs) 0.85 mg/L

Other Drugs (Sample 1) Alcohol none detected TFMPP 0.02 mg/L Diazepam 0.11 mg/L Blood Mephedrone 0.004 mg/L (approximately (,LOQ)) Other Drugs Alcohol † Blood 120 mg/dL † Urine 165 mg/dL Diazepam 0.15 mg/L 11-nor-delta-9-tetrahydrocannabinolic acid Blood Mephedrone 0.06 mg/L Other Drugs Alcohol † Blood 184 mg/dL † Urine 246 mg/dL TFMPP 0.01 mg/L Blood Mephedrone 0.003 mg/L (approximately (,LOQ)) Other Drugs Alcohol -Blood & Urine – none detected Diazepam 0.005 mg/L Blood Mephedrone 0.28 mg/L Other Drugs Alcohol † Blood 77 mg/dL † Urine 126 mg/dL Ketamine 0.26 mg/L Blood Mephedrone 0.14 mg/L Other Drugs Alcohol none detected Tramadol 0.12 mg/L Codeine 0.03 mg/L Blood Mephedrone 0.65 mg/L Other Drugs Alcohol none detected Fluoxetine 0.11 mg/L 11-nor-delta-9tetrahydrocannabinolic acid

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. There was no evidence of pre-existing natural disease or trauma. The cause of death was given as’ Mephedrone Toxicity’.

The findings were consistent with hanging. There was no evidence of natural disease.

The findings were consistent with hanging. There was no evidence of natural disease.

The findings were consistent with 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. There was no evidence of natural disease.

The trachea and main bronchi contained slightly blood-stained fluid. The lungs were expanded, had a doughy consistency and abundant fluid could be expressed from their cut surfaces. The cause of death was given as ‘Drowning’.

There was frothy pale fluid within the trachea. The lungs were expanded, over-riding the mediastinum and copious fluid could be expressed from the cut surfaces. There were no other findings of note at autopsy. The cause of death was given as ‘Drowning’.

The findings at autopsy were consistent with hanging. There was no evidence of natural disease.

Table II. 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. Subject & Story

Observed Symptoms

Time Lapse (Hours)

Mephedrone Levels (mg/L)

Case1 26 y/o old male. 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.

unknown

0.66

Case 2 25 y/o male, arrested in his vehicle due to public reports of a burglary. 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.

1.5

0.65

Case 3 31 y/o male, observed by police in a badly parked car. A bag of white powder labelled ‘plant food’ was seized from the vehicle’.

Subject had glazed eyes and slurred speech. He undertook a FIT test which he failed.

2.0

0.43

Case 4 31 y/o male, stopped as he attempted to avoid police at a vehicle check-point. Subject handed over a bag of white powder he stated was ‘mephedrone’.

Subject had glazed eyes.

1.5

0.19

Case 5 21 y/o male, arrested for theft in supermarket after driving to the store. 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.

3.0

0.16

Case 6 22 y/o male, stopped by police due to nature of driving.

Subject had dilated pupils and was unsteady on his feet.

1.5

0.12

Case 7 29 y/o male, stopped by police for driving erratically and without headlights in poor conditions. A package with white powder was found in the car. On arrest subject claimed, ‘I had 1 gram of mephedrone and I’ve had half of that - I snorted it’. Herbal cannabis was also seized from the subjects address.

Subject had slurred speech and glazed eyes.

2.5

0.10

Case 8 19 y/o male, found asleep with 2 passengers in the drivers seat of a vehicle. Subject possessed a small bag of white powder he said was ‘mephedrone’. Other drug paraphernalia was found in the vehicle.

Subject was uncoordinated and had slurred speech. Subject also failed a preliminary impairment test.

2.5

0.09

Case 9 26 y/o male, driving erratically, swerving across lanes. The subject admitted taking ‘mephedrone’. A bag containing white powder was also found in the subject’s sock. This was later identified as 0.5 grams of mephedrone.

His eyes were glazed and rolling in his head and he appeared dazed and confused with slurred speech.

2.0

0.08

hyperthermia (428C), developed complete organ failure and died the following day, 16 h after admission. His postmortem blood concentration was 8.4 mg/L. No other drugs or alcohol were detected in either case. In a recent paper by Maskel et al. (10), four mephedronerelated deaths were described. 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 2.24 mg/L). A low concentration of trifluoromethylphenylpiperazine (TFMPP) was also found in the blood. 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. Death from acute amphetamine poisoning does not usually ensue immediately, but after a period of several hours, during

which time the subject experiences agitation, hyperthermia, convulsions, unconsciousness and respiratory and/or cardiac failure (11). In a study of 17 deaths attributed solely to amphetamine, femoral blood concentrations ranged from 1.1 – 7.4 mg/L (12). 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 2.1 mg/L. In Case 6, antemortem samples were analyzed, the earliest of which had a mephedrone concentration of 1.94 mg/L. 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.


Table III. Results of the impaired driving cases, in which mephedrone was found along with other drug(s) /alcohol. Time lapse refers to the time between the incident and the blood sample being taken. All samples were whole blood. Subject and Story

Observed Symptoms

Time lapse(Hours)

Drug levels (mg/L)

Case 10 22 y/o male stopped by police as vehicle tax had expired. Unidentified white powder and a copper pipe ‘sniffer’ were seized from the subject.

Powder was observed around subject’s nostrils, foam around the mouth, eyes constricted. Subject was drowsy and at times his speech was incoherent.

2.0

Mephedrone 0.74 Diazepam 0.15

Case 11 24 y/o female involved in a single vehicle crash. The subject was found at the hospital.

Subject admitted to taking citalopram and snorting ‘mephedrone’ previous to driving.

4.0

Mephedrone 0.58 Benzoylecgonine 0.06 Citalopram 0.16 Diazepam 0.05 Cyclizine 0.07

Case 12 22 yr old male stopped by police at a vehicle check-point. The subject admitted to smoking a couple of ‘joints’ before driving.

The subject was nervous and agitated; his eyes were glazed and bloodshot. He was distracted with slurred speech and a dry month.

1.5

Mephedrone 0.42 THCCOOH (11-nor-delta-9-tetrahydrocannabinolic acid)

Case 13 32 y/o male was arrested by police after a member of the public commented on the subjects driving and observed him crash into a parked car causing extensive damage.

Police observed white powder under the subject’s nose. He was agitated with dilated pupils and slurred speech.

6.0

Mephedrone 0.41 Benzoylecgonine 0.12 TFMPP 0.02 (Trifluoromethylphenylpiperazine) THCCOOH

Case 14 21 y/o male stopped by police with regards to a defective light. The subject was carrying a small bag containing white powder which he believed to be ‘magic’.

The subject’s eyes were glazed and his behaviour was erratic.

2.0

Mephedrone 0.4 Diazepam 0.8

Case 15 19 yr old male arrested as a result of a 2-car collision.

The subject had diluted pupils, glazed eyes and slurred speech. He appeared unsteady on his feet.

2.0

Mephedrone 0.3 THCCOOH

Case 16 21 yr old male stopped by police for erratic driving. A small bag of powder was found in the car; the subject stated ‘it’s plant food’.

Subjects behaviour was erratic, he had glazed eyes and slurred speech.

5.5


Case 17 a young female was arrested after police were tasked to a single vehicle collision causing damage to private property. The subject admitted to drinking alcohol and taking prescribed diazepam.

The subject had slurred speech and smelt of intoxicating liquor.

3.0

Mephedrone 0.18 Alcohol (breath)38 ug/100 mL

Case 18 31 y/o male stopped by police due to public concerns over the nature of his driving. 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.

1.5

Mephedrone 0.14 THCCOOH Benzoylecgonine 0.04

Case 19 19 yr old male stopped at a vehicle check-point. During a search of the vehicle, 27 capsules containing yellow powder and a small bag of yellow powder were seized. The subject believed these to be a ‘legal high’. The powder was confirmed as mephedrone and the capsules as TFMPP and BZP.

The subject’s pupils were pin -point and he had yellow powder on his tongue.

3.5


Case 20 26 y/o male. 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.

2.5

Mephedrone 0.1 Alcohol (blood) 102 mg/dL

Case 21 22 yr old male stopped by police after they observed him crash into a petrol pump. tramadol and diazepam tablets were seized from the vehicle.

The subject had difficulty standing unaided. His speech was slurred and his eyes were bloodshot and appeared heavy. The subject failed a FIT test.

unknown

Mephedrone 0.1 Diazepam 1.2, Tramadol 0.07 Temazepam 0.19

Case 22 20 yr old male stopped by police due to erratic driving and weaving across lanes. 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.

2.5


Case 23 31 y/o male stopped routinely by police. 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.

2.0

Mephedrone 0.05 THCCOOH Naphyrone (low level)

Case 24 30 y/o male stopped walking from his car due to suspicious behaviour. 4 white capsules were found in the subject’s possession. He said they were ‘herbal-like speed that gives a legal high’. 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.

2.5


Case 25 21 y/o male, stopped by police after being reported for fuel theft.

Subject had slurred speech was unsteady on his feet and had white powder under both nostrils.

4.0

Mephedrone 0.05 Nordiazepam 0.08 THCCOOH

Diazepam 1.53

(continued)

80 Cosbey et al.

Table III. Continued Subject and Story

Observed Symptoms

Time lapse(Hours)

Drug levels (mg/L)

Case 26 21 y/o male abandoned vehicle after a single vehicle collision. Subject was later brought to police station by his father. The subject claimed to have taken ‘herbal coke’ before driving.

Subject had glazed eyes, his speech was incoherent and he appeared irrational.

6.5

Mephedrone 0.04 BZP 0.03 (benzylpiperazine) TFMPP 0.01 Diazepam 0.39

Case 27 20 y/o male was ‘joy-riding’ and subsequently arrested by police after a long pursuit. 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.

2.0

Mephedrone 0.03 Alcohol (blood) 102 mg/dL THCCOOH

Case 28 24 y/o male, arrested for taking a vehicle without consent. 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.

1.5

Mephedrone 0.01 Alcohol (blood) 99 mg/dL Tramadol 0.59 THCCOOH

Case 29 29 y/o male drove away from police and was observed driving erratically, swerving over the lines. A bag containing several blue tablets was found in his possession.

Subject was swaying and unsteady on his feet.

1.0

Mephedrone 0.01 Diazepam 5.0 THCCOOH

Case 30 19 y/o male stopped by police at vehicle check point and found with 13 bags of white powder, confirmed to be mephedrone.

unknown

3.0

Mephedrone low level THCCOOH

Case 31 20 y/o male arrested for suspicious behaviour in court building, having admittedly driven there. 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.

3.0

Mephedrone low level Diazepam 1.1 Amphetamine 0.02

Case 32 21 yr old male arrested for a damage only hit and run.

Subject was unsteady, had glazed eyes and slurred speech.

unknown

Mephedrone low level Diazepam 1.1

In Case 6, many antemortem samples were taken over a period of 3.5 h, allowing an approximation to be made of drug elimination characteristics. This estimation of 3– 4 h appears to be a little shorter than the published elimination half-lives of other amphetamine-like drugs (11). 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 0.003 to 0.65 mg/L (mean 0.16, median 0.08). 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 the impaired driving cases considered in this study, the time interval between the incident/observation and the collection of the blood sample is likely to have been relatively short (within a few hours). 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. Of the nine cases in this category, police and/or witness observations consistently report such symptoms as hurried and slurred speech, agitation and hyperactivity or glazed eyes. The highest mephedrone concentrations reported in these cases were 0.66, 0.65 and 0.43 mg/L; in each of these cases, the driver failed an objective field impairment test (FIT)

Table IV. Results of 3 impaired driving cases with high mephedrone concentrations and other drugs present. All samples were whole blood. Age/gender

Time interval(Hrs)

Observed Symptoms

Mephedrone (mg/L)

Other drugs (mg/L)

1

22/male

2.0

0.74

Diazepam 0.15

2

24/female

4.0

Constricted pupils, drowsiness, incoherent speech Hospitalized after collision

0.58

3

22/male

1.5

Nervous & agitated eyes glazed & bloodshot**, slurred speech, dry mouth

0.42

Benzoylecgonine 0.06 Citalopram 0.16 Diazepam 0.05 Cyclizine 0.07* THCCOOH

* hospital treatment ** likely caused by cannabis

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. All samples were whole blood. Mephedrone Range (mg/L) Impaired Driving Mephedrone only Impaired Driving Mephedrone þ other drugs Impaired Driving (All cases) Mephedrone in fatal cases fatality not directly attributed to the drug

Mephedrone Mean (mg/L)

Mephedrone Median (mg/L)

0.08– 0.66

0.27

0.16

0.01– 0.74

0.18

0.10

0.01 – 0.74

0.21

0.10

0.003 – 0.65

0.16

0.08


conducted by a police officer. The blood concentrations found in the nine cases (reported time interval up to 3 h) ranged from 0.08 to 0.66 mg/L (mean 0.27 mg/L, median 0.16 mg/L). In a subset of these results (cases associated with a time interval of less than 1.5 h), the mean mephedrone concentration was found to be slightly higher (as expected), with mean of 0.32 mg/L and median of 0.19 mg/L. Of the 23 cases in this category, the cases with the highest mephedrone concentrations are outlined in Table IV. In all of the cases in this category (n ¼ 23), mephedrone concentrations ranged from 0.01 to 0.74 mg/L (mean 0.18 mg/L, median 0.10). In the seven cases in which the time interval was less than 1.5 h, the mephedrone concentrations ranged from 0.01 to 0.42 mg/L (mean 0.18 mg/L, median 0.14). The data from all impaired driving cases are tabulated in Table V. The negative bias associated with the median values indicates that the overall composition of the data sets is biased toward lower values.

Conclusions This study presents mephedrone concentrations in both fatal and impaired driving casework. Subjects were predominantly young adult males. Alcohol was involved in 12% of impaired driving cases. In all impaired driving cases (n ¼ 32), blood concentrations ranged up to 0.74 mg/L, with mean and median mephedrone concentrations of 0.21 and 0.10 mg/L, respectively. In the impaired driving cases in which mephedrone was the only drug detected (n ¼ 9), blood concentrations ranged up to 0.66 mg/L, with mean and median mephedrone concentrations of 0.27 and 0.16 mg/L, respectively. In those fatal cases (n ¼ 2) in which death was attributed directly to mephedrone toxicity alone, blood mephedrone concentrations were both approximately 2.0 mg/L. 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 2.24 mg/ L). In this case, a low level of TFMPP was also detected. The evidence presented in this study indicates that recreational use of mephedrone can produce to blood concentrations

82 Cosbey et al.

at least as high as 0.75 mg/L, although the average value encountered is likely to lie between 0.2 and 0.3 mg/L. On the basis of the data presented, fatality due to mephedrone alone is likely to be associated with blood mephedrone concentrations of greater than 2.0 mg/L. 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.

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