Introduction

In order to circumvent existing legislation on controlled substances, derivatives of known psychoactive substances began to appear on the black market as “designer drugs” in the mid-2000s [1, 2]. One popular family of designer drugs are the synthetic cathinones or “bath salts”. 3,4-methylenedioxypyrovalerone (MDPV) is a member of this family: a β-keto phenylalkylamine, derivative of the natural alkaloid cathinone found in the plant Catha edulis (khat) [1, 3]. MDPV, initially synthesized by Boehringer Ingelheim in 1969 [1], was first detected in Japan in 2006, and subsequently was increasingly found throughout the world [4, 5]. In 2011, the Drug Enforcement Agency of the United States (DEA) scheduled MDPV on a temporary emergency basis [6, 7]. Since this time, the prevalence of MDPV in synthetic cathinones decreased in favor of unregulated compounds.

Synthetic cathinones are stimulants consumed for the effects of increased alertness and energy, euphoria, excitement, improved mood, sociability and intensification of sensory experience (mild empathogenic effects) [5]. Undesired cardiac and neurological effects include tachycardia, hypertension, cardiac arrest, agitation, aggressive and combative behavior, disorientation, confusion and paranoia [1, 5,6,7,8,9,10].

The physical form of MDPV is a white, tan, gray, yellow or brown odorless powder [1, 6] and is often mixed with caffeine and lidocaine or benzocaine [5]. It is marketed as “bath salt” (in the US) or “plant feeder” (in Europe) and sold under 50 different known brand names on the Internet or in head shops, convenience stores, gas stations and tobacco shops [5, 6, 11, 12]. Its main modes of ingestion are oral, intravenous, insufflation (snorting) and inhalation (smoking) [1, 5, 6, 8, 13,14,15]. Doses of 5 to 30 mg in a single ingestion are typical [1, 5, 8], with effects lasting 1 to 3 h [10].

Although several clinical cases of consumption of, or intoxication by, MDPV have been reported [4, 9, 12, 13, 15,16,17,18,19,20,21], there are only a few fatal MDPV intoxication cases published with toxicology results [3, 6, 10, 14, 22, 23]. In all of these cases, the MDPV concentration was elevated (>80 ng/mL in whole blood). We present here a case of fatal idiosyncratic reaction to MDPV, a radically different type of MDPV intoxication than what has been previously published.

Case history

Background

The victim was a 42 year old Native American male that had been incarcerated for several months prior to the event. In the early afternoon, the man was standing in front of his cell, talking incoherently. He then approached the guards’ post and became hysterical and disorganized. Prison personnel attempted to physically control him, but he fought them vigorously. He was eventually cuffed at the wrists and ankles and put into a padded cell, lying on his side. 27 min later, the man was in cardiorespiratory arrest and resuscitation maneuvers were started. Upon arrival at the hospital, 1 h19 into the event, the victim’s rectal temperature was 39.3 °C. His death was pronounced 1 h40 after the beginning of the event. Since the victim was in cardiac arrest upon arrival at the hospital, no biochemistry or toxicology screen was performed.

Autopsy findings

The deceased was 182 cm tall and weighed 156 kg. The external exam revealed the presence of linear abrasions and light bruises at the wrists and ankles, most likely due to the cuffs placed on the victim. Also, numerous bruises were observed on the four limbs, which could have resulted from confinement of the victim by the prison personnel or have been auto-inflicted. A linear abrasion on the shoulder blade and abrasions on the knees were also observed. No other significant traumatic lesions were apparent on external examination.

The internal exam revealed the presence of left pleural adhesions. The heart weighed 520 g and revealed a slight left ventricle hypertrophy, without any congenital anomaly, valvular or coronary disease. The lungs (right 820 g, left 870 g) were heavy and congested, which was confirmed through histological analysis. The liver weighed 1780 g and was affected by steatosis without associated cirrhosis, which was also confirmed by the histological exam. The urinary bladder contained 80 mL of urine. The full length of the gastro-intestinal tract was opened and no intra-luminal body was found. Gastric contents (60 mL) were a brownish liquid with beige, black and green particles. Rib fractures attributed to CPR were observed. No cranial, spine, hip or limb fractures were seen. No other anatomic lesions were observed.

Toxicological analysis

Peripheral blood from the femoral vein, cardiac blood (pooled from both ventricles), urine, gastric contents and vitreous humor were recovered for toxicological analyses. Toxicology included cyanide screening, ethanol and volatile compound determination, immunological screening (cocaine, opiates, PCP, amphetamines, cannabinoids, barbiturates, salicylates, benzodiazepines, acetaminophen, paracetamol and methadone) as well as gas-chromatography-mass spectrometry (GC-MS-NPD) screening and liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantification. All of these methods (unpublished) are validated, and the quantitative methods are accredited under ISO 17025/CAN-P 1578 standards. To carry out the LC-MS/MS analysis, all matrices were extracted with a protein precipitation protocol using a mixture of acetonitrile and acetone as the precipitating agent. Results of the toxicological investigation are shown in Table 1.

Table 1 Postmortem toxicological analysis results
Full size table

Also detected in cardiac blood, femoral blood and urine were the metabolites demethylenyl-methyl-MDPV, N-desmethylmirtazapine and THC-COOH glucuronide. According to medical records, the victim had a prescription for mirtazapine and clonazepam, explaining the presence of these two compounds in the toxicology results.

By taking into account circumstances surrounding death (agitation, violent behavior, hyperthermia) and toxicology results, the cause of death was ruled to be complications of an adverse reaction to consumption of MDPV by the victim. It was also noted that the pre-existing medical condition of the victim (obesity, slight cardiac hypertrophy) may have contributed to death.

Subsequent toxicological screening by liquid chromatography-time of flight mass spectrometry (LC-QToF) initially suggested the presence of 4-acetoxy-DMT (4-AcO-DMT) in cardiac blood and urine via a library hit. 4-acetoxy-DMT (also known as psilacetin and O-acetylpsilocin) is a synthetic pro-drug of the hallucinogenic compound psilocin [24]. However, further analysis using reference material confirmed this as a false positive, since retention time did not match and specific fragments were absent.

Discussion

A certain number of MDPV intoxication cases have already been published in the literature (see Table 2). In all published reports, the MDPV concentration in blood is more elevated than what was observed in the case presented here. Indeed, all but one case show MDPV concentrations at least 10 times higher than the 6 ng/mL found in the cardiac and femoral blood of the victim. Although an MDPV overdose (in the strictest sense of the term) seems unlikely here, an adverse reaction to MDPV is a probable mechanism of death.

Table 2 Previously published MDPV fatal intoxications
Full size table

MDPV is a dopamine and norepinephrine reuptake inhibitor acting as a stimulant [1, 7, 9, 22]. In vitro transporter assays performed on brain synaptosomes show that MDPV functions as a monoamine uptake pure blocker (like cocaine) and not as a monoamine transporter substrate (like amphetamine) [25]. The pharmacology of MDPV is thus closer to cocaine than MDMA, as was previously thought.

It is well known that there is no “safe” concentration for cocaine, since virtually any concentration can trigger an adverse reaction and ultimately death [26]. Given the similarity between the pharmacology of MDPV and cocaine, it would seem logical that a similar potential for adverse reactions exists with MDPV.

Stimulant drug use, particularly cocaine, is a known trigger of excited delirium syndrome (ExDS), even at recreational dosages [27]. Excited delirium syndrome is characterized by an excited or agitated state, delirium, sometimes complemented by tachycardia and hyperthermia followed by cardiac arrest [3, 27]. The behavior reported by prison personnel as well as the hyperthermia highlighted at the hospital both fit the ExDS profile. The exact mechanism of this potentially lethal side effect is unknown. The observed hyperthermia is thought to result from dysregulation of the dopaminergic pathways in the hypothalamus [3] and has been reported in an elevated number of MDPV intoxications and adverse reactions [3, 4, 6, 9, 16, 17, 23]. The presence of ExDS adds to the profile of an adverse reaction to a stimulant. It is worth noting that the presence of mirtazapine, even at therapeutic concentrations, might have contributed to the elevation of serotonin levels and thus the reported agitation of the victim.

Demethylenyl-methyl-MDPV (also called methyl cathecol pyrovalerone [2]) has been previously identified in studies of in vitro human liver microsomes and in vivo rat MDPV metabolism [2, 28]. It is hypothesized to result from the methylation of the initial demethylenyl-MDPV metabolite produced by CYP 1A2, CYP 2C19 and CYP 2D6 [28] enzymes. The lack of additional metabolite standards limited LC-MS/MS analysis for identification and quantification of other metabolites besides demethylenyl-methyl-MDPV in the matrices.

In the case reported here, several elements point towards a case of fatal idiosyncratic reaction to the stimulant designer drug MDPV, such as excited delirium syndrome with hyperthermia, low concentrations of MDPV in blood and the similarity of the pharmacology of MDPV with cocaine. This is a category of MDPV intoxication previously unreported in the literature.

Key points

  1. 1.

    3,4-methylenedioxypyrovalerone (MDPV) is a stimulant designer drug with a pharmacology similar to cocaine.

  2. 2.

    Excited delirium syndrome (ExDS) is characterized by agitation, delirium, tachycardia and hyperthermia. A common trigger is stimulant drug consumption.

  3. 3.

    Presence of ExDS with recreational MDPV concentrations should be considered as indications of a potential adverse reaction to MDPV.