A fatal paramethoxymethamphetamine intoxication

doi:10.1016/S1344-6223(02)00096-2

Legal Medicine

Volume 5, Supplement, March 2003, Pages S138-S141

https://doi.org/10.1016/S1344-6223(02)00096-2 Get rights and content

Abstract

During the last years in Germany a marked increase in the use of amphetamines such as 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been observed. The use of these recreational drugs is especially common among young people participating in rave parties. Occasionally ring-methoxylated phenethylamine derivatives like paramethoxymethamphetamine (PMMA) or paramethoxyamphetamine (PMA) are found in street drugs offered as ecstasy. These compounds exhibit a higher toxicity than the methylenedioxyamphetamine derivatives. We report on the death of a 22-year-old man after the ingestion of ecstasy pills containing PMMA and PMA. The PMMA concentration in femoral blood was 0.85 mg/l. Besides PMA (0.61 mg/l), amphetamine (0.21 mg/l), benzoylecgonine (<0.01 mg/l) and ethanol (0.46 ‰) were found in the blood. The case reflects the well-known fact that street drugs offered as ecstasy pills contain not necessarily MDMA but frequently differ in composition even if they have the same logo. Users of these pills therefore always take the risk of consuming pills with dangerous life-threatening ingredients. In many laboratories paramethoxyamphetamines are not detectable in routine analytical procedures. If the cause of an intoxication cannot be discovered by analytical routine methods, rarely occurring designer drugs such as PMA or PMMA should also be kept in mind.

Introduction

The ring-methoxylated phenethylamine derivatives paramethoxyamphetamine (PMA) and paramethoxymethamphetamine (PMMA) are structurally related to mescaline and to the compounds of the so-called ecstasy group including 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethylamphetamine (MDEA). PMA and PMMA, two powerful stimulants, are cheaper and easier to manufacture than ecstasy and far more dangerous. These drugs all exhibit hallucinogenic properties. During the last years in Germany a marked increase in the use of amphetamines such as ecstasy has been observed. The use of these recreational drugs is especially common among young people participating in rave parties. Occasionally PMA and PMMA occur among pills being sold as ecstasy. Many of these pills are stamped with a three-diamond Mitsubishi logo.

Section snippets

Case history

A 22-year-old man died after the ingestion of ecstasy pills containing PMMA and PMA. The young man was witnessed to be hallucinating at a party. Later, he started to convulse and developed respiratory distress. An ambulance was called but an attempted resuscitation failed. Police inquiry revealed that the deceased had a past history of occasional use of cannabis. At autopsy no evidence of any disease that might have caused death was found. A typical mark of venipuncture was seen on the left

Experimental

Screening of urine was performed using fluorescence polarization immunoassay (FPIA) on the Abbott ADx analyzer (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates, tricyclics), the automated drug-profiling system REMEDi (Bio-Rad Laboratories) and gas chromatography–mass spectrometry (GC/MS). Ethanol was quantified by means of standard GC (head space) and enzymatic (ADH) methods. Quantification was done with a routinely used analytical method for the

Results and discussion

Routine screening of urine by immunoassay techniques revealed the presence of a high level of amphetamines and trace amounts of cocaine metabolites. HPLC screening of urine with REMEDi identified parahydroxymethamphetamine. It is used in Germany for the treatment of hypotension and available without prescription (Pholedrin). The second larger peak could not be identified by the REMEDi library. The following GC/MS screening of urine then identified high amounts of PMA and PMMA as well as

References (4)

J. Becker et al.
Simultaneous determination of frequently abused illicit drugs in serum and other body fluids. IV International Symposium Advances in Legal Medicine 22.09–25.09 in Mainz
Rechtsmedizin
(1999)
J. Röhrich et al.
Effect of the shampoo Ultra clean on drug concentrations in human hair
Int J Legal Med
(2000)

There are more references available in the full text version of this article.

Cited by (29)

Synthetic amphetamine derivatives, benzofurans, and benzodifurans
2021, Novel Psychoactive Substances: Classification, Pharmacology and Toxicology
Synthetic amphetamine derivatives, benzofurans, and benzodifurans are commonly used, ever-growing number of synthetic substances. This chapter reviews the pharmacology, prevalence of use worldwide, as well as evidence of toxicity in animals, and in humans, using case reports of toxicity and deaths when available, with a goal of providing a better understanding of availability, abuse potential, and burden of toxicity from common forms of these substances.
Amphetamine derivatives share a common phenylethylamine chemical skeleton that, with subtle structural modifications, can result in a diverse array of drugs capable of producing varied and discrete clinical effects. The mechanism of action of these agents is stimulated release of biogenic amine neurotransmitters, inhibition of their reuptake, and prevention of their degradation. The paucity of reliable medical information regarding the effects of novel amphetamine derivatives in humans underscores both the need for confirmatory testing in suspected cases and for the clinician to be familiar with structure activity relationships and their expected physiological result. In this chapter we review experimental animal data, self-reported human clinical effects and existing case reports and case series to highlight the clinical effects of amphetamine derivatives. This is a continuingly developing field with new drugs being developed and marketed on an ongoing basis. Drugs are therefore classified by chemical and clinical similarity to assist clinicians with the prediction of potential adverse effects as newer drugs continue to emerge.
Benzofurans are members of the amphetamine and phenylethylamine classes. 6-APB and 5-APB have recently been identified as single furan ring benzofuran compounds used as recreational drugs, producing sympathetic system stimulation and euphoria. There is little information available regarding their toxicity. They are postulated to exert their effects through stimulation of catecholamine receptors and as 5-HT receptor agonists. Benzodifurans (containing 2 heterocyclic rings) including bromo‑dragonFLY and 2-CB-FLY are ring-substituted phenylethylamines with potent 5HT_2A agonist effects and predominant hallucinogenic clinical effects. Bromo-dragonFLY toxicity produces excess sympathomimetic activity and severe vasoconstriction, in some cases resulting in limb amputation. Deaths secondary to bromo‑dragonFLY and mis-identified 2-CB-FLY (containing bromo‑dragonFLY) have occurred in Europe and the USA. Recent surveys of drug users indicate that 6-APB is the most commonly used recreational benzofuran in the UK; although compared to established, classical recreational drugs and other novel psychoactive substances 6-APB and other drugs in this class are rarely used.
Cytotoxicity of new psychoactive substances and other drugs of abuse studied in human HepG2 cells using an adopted high content screening assay
2019, Toxicology Letters
Citation Excerpt :
Cmax values for NPS are usually not available due to lack of controlled studies. Hence, described common user's doses and/or plasma concentrations from case reports (0.01–1 μM) (Abouchedid et al., 2016; Araujo et al., 2015b; Becker et al., 2003; Corkery et al., 2013; Kesha et al., 2013) were used for rough assessment of their expected Cmax values. For the cytotoxicity prescreening, only two concentrations, a lower (10 μM) and a higher (100 μM) one were applied.
New psychoactive substances (NPS) are still an emerging issue in clinical and forensic toxicology. Information about their cytotoxic potential is limited or even unavailable before distribution and thus their intake can be of high risk for consumers. The aim of the presented study was to develop a strategy to identify cytotoxic potential of NPS based on a high content screening assay (HCSA) using HepG2 cell line and four fluorescent dyes, namely Hoechst33342, TMRM, CAL-520, and TOTO-3. The HCSA was optimized to work without an automated analyzer by using the model compounds fluvastatin, paracetamol, propranolol, and simvastatin. The following parameters were monitored: stained nuclei as a measure for cell count as well as nuclear size and nuclear intensity (all Hoechst33342), mitochondrial membrane potential (TMRM), cytosolic calcium level (CAL-520), and plasma membrane integrity (TOTO-3). The present study showed strong cytotoxic potential for the NPS 5F-PB-22 and MDAI, moderate effects for MDMA, MDPV, methylone, cathinone, 4-MEC, and mephedrone, and no toxic effects for methamphetamine. To assess the metabolic suitability of HepG2 cells under the chosen conditions, cell culture supernatants were analyzed by liquid chromatography-high resolution-tandem mass spectrometry. Metabolites were merely detected for lipophilic drugs such as 5F-PB-22 and MDPV and in addition with a much lower abundance in comparison to the parent compound but the study only allowed a qualitative look for metabolites and the used liver cell line might not ideal when considering metabolism.
Screening of seized emerging drugs by ultra-high performance liquid chromatography with photodiode array ultraviolet and mass spectrometric detection
2014, Forensic Science International
Citation Excerpt :
Over the past few years, the use of new synthetic psychoactive designer drugs has exploded due to their easy access via the Internet and at local “head shops” [3–5]. Since most of these drugs are new and have little or no safety and toxicological data, many overdoses and bizarre effects from mis-use have been reported [6–9]. Legislation has been put in place in many countries to address this problem.
The use of psychoactive “designer drugs” has increased rapidly due to their varying and sometimes ambiguous legal status and their ready access via the Internet and at local “headshops.” A quick screening method for samples containing these substances, using ultra-high performance liquid chromatography with photodiode array UV and mass spectrometric detection (UHPLC-PDA/UV–MS), is presented. The method enables the screening of a variety of samples containing emerging/reemerging drugs, including β-keto phenethylamines (cathinone derivatives), synthetic cannabinoids/cannabimimetics, and phenethylamine derivatives. The use of dual detectors not only provides molecular weight information but also differentiates the drugs by their categories and in some cases even their sub-categories. Moreover, ring positional isomers of cathinone and phenethylamine derivatives can be easily differentiated by their retention times and UV spectra.
Synthetic Amphetamine Derivatives
2013, Novel Psychoactive Substances: Classification, Pharmacology and Toxicology
Amphetamine derivatives share a common phenylethylamine chemical skeleton that, with subtle structural modifications, can result in a diverse array of drugs capable of producing varied and discrete clinical effects. The mechanism of action of these agents is stimulated release of biogenic amine neurotransmitters, inhibition of their reuptake, and prevention of their degradation. The paucity of reliable medical information regarding the effects of novel amphetamine derivatives in humans underscores both the need for confirmatory testing in suspected cases and for the clinician to be familiar with structure activity relationships and their expected physiological result. In this chapter we review experimental animal data, self-reported human clinical effects and existing case reports and case series to highlight the clinical effects of amphetamine derivatives. This is a continuingly developing field with new drugs being developed and marketed on an ongoing basis. Drugs are therefore classified by chemical and clinical similarity to assist clinicians with the prediction of potential adverse effects as newer drugs continue to emerge.
Analytical Techniques for the Detection of Novel Psychoactive Substances and Their Metabolites
2013, Novel Psychoactive Substances: Classification, Pharmacology and Toxicology
The emergence of ever-novel psychoactive substances on the recreational drug market is an ongoing challenge for analytical toxicologists. If still unknown, their structure must first be elucidated. Once this has been achieved and reference substances have become available, it is important that laboratories working in the field of clinical and forensic toxicology either update existing methods or develop new ones that cover the novel psychoactive substances (NPS). This chapter provides an overview of analytical methods for analysis of NPS in biological matrices such as blood, urine and hair and discusses pitfalls and interpretative issues. It includes analytical methods covering compounds from several drug classes as well as methods dedicated to analysis of compounds from the following drug classes: piperazines, 2,5-dimethoxyphenethylamine-derived drugs (2Cs), 2,5-dimethoxyamphetamine-derived drugs, 4-substituted amphetamines, β-keto-amphetamines (cathinones), pyrrolidinophenones, tryptamines, and synthetic cannabinoid receptor agonists. Finally, some recommendations for setting up procedures for analysis of NPS are given.
The PMMA epidemic in Norway: Comparison of fatal and non-fatal intoxications
2012, Forensic Science International
Citation Excerpt :
In 11 of these fatalities, the PMMA concentrations were above 0.5 mg/L, and in most cases greater than 1.24 mg/L. These are high PMMA concentrations within the fatal range reported by other authors [1,8–12]. For comparison, PMMA or PMA blood concentrations above 0.5 mg/L are reported to be associated with toxic and possibly lethal effects [13,14].
During a 6 month period (July 2010–January 2011) we observed 12 fatal intoxications and 22 non-fatal cases related to the drug paramethoxymethamphetamine (PMMA) in Norway (4.8 mill inhabitants). This toxic designer drug, also known as “Death”, is occasionally found in street drugs offered as “ecstasy” or “amphetamine”. The present study aimed to evaluate the cause of death, and to compare the PMMA blood concentrations in fatal and non-fatal cases. Methods for identification and quantification of PMMA are presented. The median age of fatalities was 30 years (range 15–50) with 67% males; in non-fatal cases 27 years (20–47) with 86% males. In the 12 fatalities, the median PMMA blood concentration was 1.92 mg/L (range 0.17–3.30), which is in the reported lethal range of 0.6–3.1 mg/L in peripheral blood and 1.2–15.8 mg/L in heart blood. In the 22 non-fatal cases, the median PMMA concentration was 0.07 mg/L (range 0.01–0.65). Poly-drug use was frequent both in fatal and non-fatal cases. The PMA concentrations ranging from 0.00 to 0.26 mg/L in both groups likely represented a PMMA metabolite. Three fatalities were attributed to PMMA only, six to PMMA and other psychostimulant drugs, and three to PMMA and CNS depressant drugs, with median PMMA concentrations of 3.05 mg/L (range 1.58–3.30), 2.56 (1.52–3.23) and 0.52 mg/L (0.17–1.24), respectively. Eight victims were found dead, while death was witnessed in four cases, with symptoms of acute respiratory distress, hyperthermia, cardiac arrest, convulsions, sudden collapse and/or multiple organ failure. In summary, all fatalities attributed to PMMA had high PMMA blood concentrations compared to non-fatal cases. Our sample size was too small to evaluate a possible impact of poly-drug use. A public warning is warranted against use and overdose with illegal “ecstasy” or “speed” drugs.

View all citing articles on Scopus

View full text

A fatal paramethoxymethamphetamine intoxication

Abstract

Introduction

Section snippets

Case history

Experimental

Results and discussion

Simultaneous determination of frequently abused illicit drugs in serum and other body fluids. IV International Symposium Advances in Legal Medicine 22.09–25.09 in Mainz

Rechtsmedizin

Effect of the shampoo Ultra clean on drug concentrations in human hair

Int J Legal Med