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Amb fubinaca Background

Amb fubinaca Methods

Amb fubinaca Findings

Interpretation

Funding

Synthetic cannabinoids are a chemically diverse group of substances active at CB1 and CB2 cannabinoid receptors, designed to mimic the effects of cannabis [

,

,

]. They are a major category of new psychoactive substances (NPS) monitored by the United Nations Office of Drugs and Crime (UNODC) since 2009 [

]. In a survey of American medical examiner/coroner offices between 2010 and 2014, 25 deaths were reported in which synthetic cannabinoids were toxicologically confirmed and may have contributed to death [

]. Since 2014 an increasing number of deaths associated with a variety of synthetic cannabinoids has been reported [

,

,

,

,

,

,

,

,

,

,

]. A recent review of Australian coronial deaths between 2000 and 2017 revealed 55 cases in which synthetic cannabinoid use was considered a contributory mechanism to death [

].

AMB-FUBINACA is a synthetic cannabinoid that has caused outbreaks of poisonings in New York [

] and Connecticut [

], USA, in July 2016 and Aug 2018, respectively. Although no deaths were reported in these outbreaks, AMB FUBINACA in combination with other synthetic cannabinoids (EMB-FUBINACA and 5F-ADB) has been implicated in at least two fatalities [

,

]. In late May, June and July 2017, 17 deaths associated with AMB FUBINACA were observed in Auckland, New Zealand [

]. Since then, the Northern Forensic Pathology Service of New Zealand (NFPS) has encountered periodic deaths associated with this drug. Analysis of plant material suspected to contain synthetic cannabinoids seized in New Zealand between January and December 2107 revealed AMB FUBINACA in 157 samples (64%) [

]. In 55 of these 157 samples, para-fluorophenylpiperazine (pFPP) was also detected, although it was not found in plant material with other synthetic cannabinoids. In the past, pFPP has been marketed as a “party pill” in NZ [

]. Subsequently, pFPP was detected in several blood samples from persons in NZ who had died and tested positive for AMB FUBINACA. The contribution to drug mortality of synthetic cannabinoids, specifically AMB FUBINACA alone or in combination with other substances such as pFPP, may not be fully appreciated. This outbreak presents a unique opportunity to document the characteristics of a series of deaths associated with the synthetic cannabinoid AMB FUBINACA.

There were 64 deaths associated with toxicological evidence for the use of AMB-FUBINACA in the 18-month period beginning late May 2017 and continuing through to the end of February 2019 (Fig. 1). Previously the drug had not been reported in New Zealand deaths. The peak incidence occurred in July 2017 (11 cases). By September, following a public health campaign regarding the dangers of synthetic cannabinoids, incidents dropped to a few cases per month (range 0 to 5).

AMB-FUBINACA or its metabolite was detected in four traumatic cases in which it was not a direct cause of death, although it may have contributed in terms of behavioural effects, including two motor vehicle deaths – one in a person driving erratically, and one in a pedestrian witnessed to be crawling on the side of the road before collision – and two suicidal hangings. A fifth case involved an agitated mental health patient who died during restraint in which AMB-FUBINACA acid was identified in antemortem serum. AMB-FUBINACA acid was also detected in the sudden death of an infant who had other illicit drugs detected as well, and the contribution of AMB-FUBINACA to the cause of death is uncertain. The case is noteworthy, however, because the route of ingestion appeared to be breast milk.

The four traumatic deaths, the restraint death, and infant death were excluded from the remainder of the study, yielding a total of 58 cases. Table 1 includes a brief summary of the circumstances of death of each of the 58 cases, including cause of death and toxicological findings for AMB-FUBINACA, AMB-FUBINACA acid, and pFPP.

AMB-FUBINACA is a synthetic cannabinoid of the indazole-3-carboxamide class, active at the CB₁ and CB₂ cannabinoid receptors [

]. Among the Australian coronial deaths associated with synthetic cannabinoids, the indazolecarboxamides were most common (62%) with AB-CHIMACA cited in 38% of cases. AMB-FUBINACA was cited in one instance [

]. Although outbreaks of bizarre behaviour and stupor resulting in increased visits to emergency rooms are well known with AMB-FUBINACA [

,

], we are aware of only two recent case reports of fatalities associated with AMB-FUBINACA, each combined with another synthetic cannabinoid (EMB-FUBINACA and 5F-ADB, respectively) [

,

]. We believe that this series represents the first description of an outbreak of multiple deaths associated with AMB-FUBINACA.

There is relatively little published data on blood concentrations of synthetic cannabinoids, especially in fatalities. “Typical blood concentrations” of synthetic cannabinoids are described as 0·1–10 ng/mL, while autopsy concentrations have been reported as high as 68–200 ng/mL [

]. Reported concentrations in fatalities have varied considerably with different synthetic cannabinoids [

]. In a death associated with AMB-FUBINACA in combination with EMB-FUBINACA, blood concentrations of both compounds were below detection limit (0·1 ng/mL), although various solid tissue concentrations ranged from 0·2 to 0·9 ng/g and 0·2 to 3·5 ng/g, respectively [

]. The blood concentrations encountered in our series were considerably higher than those reported with other synthetic cannabinoids, although our quantitative results were for the metabolite rather than the parent compound. In this context it is noteworthy that the concentrations of AMB-FUBINACA documented in plant material seized by NZ law enforcement during the same period were considerably higher than those reported in other outbreaks [

,

].

Deaths first appeared in late May and June of 2017, peaked in July, and then rapidly fell to a few deaths per month following a public health campaign involving the Chief Coroner and medical authorities (see Fig. 1). During 2017, ten different synthetic cannabinoids were reported in New Zealand border and domestic law enforcement seizures [

]. In the northern part of the North Island (where Auckland is located), 84% of samples were AMB-FUBINACA, compared to 15% in the southern part of the North Island and 42% in the South Island. Furthermore, samples combined with pFPP were only reported in the upper part of the North Island [

]. Thus, the outbreak corresponds with the apparent patterns of synthetic cannabinoid illicit importation, distribution and concentrations seen by New Zealand law enforcement during the same period.

Deaths occurred predominately among males, generally in their early 40′s, but with a wide age range from 17 to 64. The sex and age range are comparable with those reported in America [

] and Australia [

]. As in the Australian experience, deaths most commonly occurred in the home environment and relatively few survived to the hospital [

]. Accidental drug toxicity was the reported the cause of death in 26 of the 55 cases in Australia. Although they did not report specifically how many deaths were considered due to the effects of synthetic cannabinoids alone compared to those in combination with other drugs, they reported other drugs present in 76·4% [

]. Intoxication with AMB-FUBINACA alone was considered the primary cause of death in 34% of our cases, and in combination with another drug or alcohol in an additional 28%. Positional asphyxia due to intoxication was a reported mechanism of death in five Australian cases, comparable to our experience (two cases). Death was attributed to cardiovascular disease, most commonly atherosclerotic disease, in approximately one fifth of the cases in both the American [

] and Australian [

] experience. Giorgetti et al. [

] also noted a significant prevalence of cardiovascular disease in their review of the published literature on deaths involving synthetic cannabinoids. Cardiovascular disease was certified as either the primary or a contributory cause of death in 27 (47%) of our cases, with hypertensive and atherosclerotic disease the most common diagnosis (52%). Obesity related heart disease was cited in five cases (see Table 2).

Witness statements suggest two mechanisms of death: seizures and central nervous system (CNS) depression characterised by passing out and/or “going to sleep.” Pulmonary oedema at autopsy in this context suggests three major pathophysiological mechanisms: centrally mediated respiratory depression, neurogenic pulmonary oedema, and acute cardiac (left ventricular) failure. Pulmonary oedema due to CNS/respiratory depression is a well-recognised mechanism of death with many drugs, and the weights of the lungs in this series are compatible with those observed, for example, in opioid deaths [

]. CNS depression due to severe intoxication with AMB-FUBINACA is a likely contributory factor in the two cases due to positional asphyxia and in the case of death due to hypothermia. On the other hand, there were four instances of witnessed seizures upon smoking synthetic cannabinoids before death and a medical history of seizures following the smoking of synthetic cannabinoids in another four individuals. In the case of seizures, neurogenic pulmonary oedema may be an operative mechanism [

]. Sudden arrhythmic cardiac death seems less likely given pulmonary oedema, but one case report suggests that AMB-FUBINACA may be associated with ST elevation and acute myocardial infarction [

]. AMB-FUBINACA has been associated with a number of adverse cardiac reactions [

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,

] that may induce acute cardiac failure especially in the context of underlying heart disease. Of course, these various mechanisms need not be mutually exclusive, and different mechanisms may hold in different cases.

Approximately 36% of individuals in this series had a known history of either schizophrenia or another diagnosis on the schizophrenic spectrum, and 23 cases (40%) were on antipsychotic medications at the time of death (see Table 5). Schizophrenics are known to be at increased risk for marijuana abuse [

], and it has been suggested that the endocannabinoid system is deranged in schizophrenia [

]. Furthermore, there is evidence that psychosis and synthetic cannabinoids use may be aetiologically associated [

]. Psychosis, for whatever reason, would appear to be a significant risk factor in this outbreak of deaths.

A limitation of this study is the lack of a well-defined control group. Although we report the characteristics observed in a series of deaths associated with AMB-FUBINACA, we know very little about the population of users of synthetic cannabinoids in New Zealand. There was a corresponding increase of emergency room visits during the early phases of this outbreak, but we have little information on those who survived. How are they different, or the same, as those who succumbed?

Also, the role of competing and contributory causes of death is unclear. Others [

,

] have observed that quantitative toxicology is difficult to interpret in the postmortem context. Although mixed intoxications appeared more commonly at lower concentrations, suggesting a dose-response effect, mixed intoxications and contributory natural disease were noted across the full spectrum, and high blood concentrations were seen in trauma cases where death was not due to direct toxicity, indicating that even the highest levels seen in our series are not necessarily lethal. Furthermore, the pathophysiological effects of the drug after peak blood concentrations and during the course of drug metabolism remain largely unknown. A low concentration of the drug in blood does not necessarily exclude its role in cause of death; any more than a high level necessarily proves lethality. More research on the correlation of blood concentration of the drug and its metabolites and toxicity is needed.

In summary, we have described a recent outbreak of deaths associated with the synthetic cannabinoid AMB-FUBINACA in Auckland, New Zealand. The lethal potential of synthetic cannabinoids may not be fully appreciated, in part because they are not routinely screened for, and in part because their contribution to drug mortality may be obscured by other substances or natural disease. Mechanism of death often appeared to be due to either CNS mediated respiratory depression or seizures. However, several potential medical risk factors were identified, including heart disease, obesity, and combined intoxication, notably with alcohol. The combination of AMB-FUBINACA with pFPP may also have played a role. Other “classic” lethal drugs of abuse, such as opioids and methamphetamine were not prominent, and this group may represent a unique subgroup of drug associated deaths. A high prevalence of psychosis, notably on the schizophrenic spectrum, was identified. Additional study is needed to characterize this subgroup of drug related deaths and its associated risk factors, in order to identify prevention and treatment measures for this evolving public health problem.

The authors wish to thank the New Zealand coroners under whose jurisdiction and for whom these cases were investigated, and the technical staff of the NFPS who provided valuable technical assistance with the performance of autopsies and the management of biological samples.