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4‐Fluoroamphetamine (4‐FA) intoxication results in exaggerated blood pressure effects compared to MDMA and amphetamine: A retrospective analysis

Abstract Objective 4‐Fluoroamphetamine (4‐FA) is an amphetamine‐type stimulant, with effects comparable to amphetamine and 3,4‐methylenedioxymethamphetamine (MDMA). Severe 4‐FA‐related complications, such as cardiomyopathy, myocardial infarction, and cerebral hemorrhage, have been described. The aim of this study was to explore the cardiovascular symptoms and complications in 4‐FA and compare them to MDMA and amphetamine in intoxicated patients who presented to the emergency department (ED). Methods Between November 2015 and March 2020, all self‐reported 4‐FA, MDMA, and amphetamine‐intoxicated adult patients that presented at the ED of an inner‐city hospital in Amsterdam, were retrospectively analyzed for cardiovascular symptoms, vital parameters, cardiovascular complications, interventions, admission rate, and Poisoning Severity Score (PSS). Results A total of 582 patients were included, of which 31 (5.3%) with 4‐FA intoxication (10/31 mono‐intoxications, 32.3%), 406 (69.8%) with MDMA (59/406 mono‐intoxications, 14.5%), 100 (17.2%) with amphetamine (10/100 mono‐intoxications, 10.0%), and 45 (7.7%) with a cross intoxication of these drugs. 4‐FA mono‐intoxicated patients experienced more headache (n = 8; 80.0%) compared to MDMA (n = 2; 3.3%; P < 0.001) and amphetamine mono‐intoxicated patients (n = 0; 0.0%; P < 0.001) and their systolic blood pressure was higher (164 mm Hg ± 31 vs 139 mm Hg ± 19; P = 0.031 vs 135 mm Hg ± 22; P = 0.033, respectively). Severe 4‐FA‐related cardiovascular complications included Takotsubo cardiomyopathy (n = 1; 3.2%), subarachnoid hemorrhage (n = 1; 3.2%), and hypertensive urgency (n = 2; 6.5%). Conclusions 4‐FA intoxication‐related ED symptoms resemble MDMA and amphetamine complications, although patients presented more often with headache and hypertension. Severe 4‐FA‐related cardiovascular complications occurred in 40% of mono‐intoxications.

amphetamine. [3][4][5] The effects are described as intermediate between MDMA and amphetamine, most likely due to the more potent effect on norepinephrine and dopamine reuptake compared to MDMA and a more potent effect on serotonin reuptake compared to amphetamine. 6 Initially, 4-FA was used as an adulterant, but it became a drug of choice over the last decade. 7,8 Its prevalence of use among Dutch party-goers (15-35 years) increased rapidly from 9% in 2013 to 25% in 2016 9,10 and it showed a global presence on the drug market. 8,[11][12][13][14][15][16][17][18] Although 4-FA is an illicit drug in the Netherlands since 2017, 4-FA continued to be the most prominent novel psychoactive substance in the Netherlands in 2018, with 0.9% of all Dutch adults having used 4-FA in that year, compared to 2.8% MDMA and 1.1% amphetamine use. 19

Importance
The popularity of 4-FA might be due to the described effect as intermediate between MDMA and amphetamine. 20,21 In case reports and small case studies, serious complications, such as heart failure, cardiomyopathy, myocardial infarction, cerebral hemorrhage, seizures, hyperpyrexia, and fatalities, have been described, 6,[14][15][16][22][23][24][25] which are comparable to previously described MDMA-and amphetaminerelated complications. 5 Due to these similarities, emergency department (ED) management of 4-FA intoxications is mostly similar to MDMA and amphetamine, although specific management may be indicated based on specific clinical effects of 4-FA. 1

Goals of this investigation
This study aimed to explore the prevalence and type of symptoms and cardiovascular complications in 4-FA and compare them to MDMA and amphetamine in intoxicated ED patients.

Study design
A retrospective study.

Setting
This study was performed at the ED of OLVG hospital, an inner city hospital in Amsterdam, the Netherlands.

Measurements
Medical chart review was performed to obtain patient characteris-

Outcomes
The main outcome of the study was the prevalence of cardiovascular complications, like hypertensive urgency and hypertensive emergency, acute coronary syndrome, cardiomyopathy, and cardiogenic shock, all defined by the European Society of Cardiologist, [29][30][31][32] and intracranial hemorrhage as defined by the American Heart Society. 33 Secondary outcome measures were the differences between 4-FA, MDMA, and amphetamine mono-intoxication-related cardiovascular symptoms and complications and intoxication severity. We hypothesized that 4-FA mono-intoxication would result in significantly higher blood pressure and more frequent complications compared to MDMA and amphetamine mono-intoxication.

Analysis
Castor Approval was granted by the OLVG local ethics committee.

Characteristics of study subjects
A total of 4409 ED patients were recorded in the toxicology registry of whom 582 patients met the inclusion criteria ( Figure 1). Baseline patient characteristics are shown in Table 1 (multi-intoxications) and

Main results
Vital parameters of mono-intoxicated patients are displayed in Table 2.
Lowest measured parameters were unavailable for more than half of the 4-FA patients and were therefore not included in the statistical analysis. Headache was the most common complaint of 4-FA mono-intoxicated patients, (n = 8, 80%), This was significantly more prevalent as compared to MDMA (n = 2, 3.3%, P < 0.001) and amphetamine mono-intoxicated patients (n = 0, 0.0%, P < 0.001). No other differences in cardiovascular symptoms were found.   (Table 3, suggesting a non-significant association toward more severe complications in 4-FA-intoxicated patients).

LIMITATIONS
The symptomatic ED patients in this study were selected and catego-

DISCUSSION
The aim of this study was to explore the cardiovascular symptoms reported incidents from 15% in 2016 to 5% in 2018 in the Netherlands and the decrease in its overall use in the EU. 8,19 Interestingly, more MDMA-and amphetamine-intoxicated patients presented at the ED after the ban, compared to before, suggesting that users might have changed their drug of choice.
In summary, 4-FA-intoxicated patients in the ED present with a significantly lower heart rate, higher systolic blood pressure, and more frequent headache, compared to MDMA and amphetamine.