First Death Involving 4-Fluoroethylphenidate (4F-EPH): Case Report,User Experiences,and Review of the Related Literature

Physical Effects

Most user reports or comments compare 4F-EPH with ethylphenidate and its related analogs, especially 4F-MPH, in terms of its stimulatory properties. Although some users report it as being more euphoric than 4F-EPH others claim the contrary. It appears to be less stimulating than ethylphenidate but more recreational than 4F-MPH. Some claim to have experienced a “smooth” sensation with 4F-EPH, while others claim it made them feel “jittery.”

A sense of physical comfort and pleasant well-being are reported at moderate doses. This is similar in nature to but weaker than the feeling of euphoria generated by methamphetamine or MDMA (5). The initial “rush” caused by 4F-EPH, lasting 5 to 15 minutes, at moderate to high doses taken via intranasal, intravenous, or sublingual routes is reported to feel like a general “tingling” sensation akin to that experienced during and after orgasm. The rush may also be accompanied by a feeling that the body is lighter or floating; the sensation may continue for some time at moderate to high doses.

There are occasional comments regarding dehydration, especially regarding undissolved powder in the mouth following oral administration, especially when rubbed on the gums or taken sublingually. Regular water intake is suggested. It also can cause damage to such soft tissue. This aspect is much more commonly mentioned in terms of the nasal route of consumption. The term “caustic” is frequently used in this context but is felt to be less caustic than snorting ethylphenidate. Saline irrigation of the nasal passages is recommended.

The cardiac and circulatory systems are subject to effects including vasoconstriction in the lower limbs, a moderate increase in blood pressure compared to 4F-MPH, and increased heart rate, especially at higher doses. Pupils may dilate, especially at higher doses; tightness around the eyes has been reported.

An increase in libido is reported at low to moderate doses, but a decrease can be noticed, especially at higher doses. Higher doses may also induce suppression of orgasm, mainly in male consumers; the latter may also experience temporary erectile dysfunction.

Cognitive Effects

A range of effects can be included under this heading. A lower “cognitive boost” is reported compared to other “phenidates.” Some users just report an experience of wakefulness, but this is considered less strong than “methylphenidate, amphetamine, and most other dopaminergic stimulants” (5).

“Thought acceleration” is regarded as mild to moderate, tending “towards semantic, emotional, social, and abstract thought patterns” (5). Occasionally users report some degree of confusion, with a noticeable decline in understanding basic concepts and remembering simple sequences. Analytical ability may be enhanced by 4F-EPH but only for routine administrative tasks rather than logical activities such as mathematics.

Some users of 4F-EPH report being energized and able to tackle routine household chores or mundane tasks without losing focus or becoming distracted. In this sense, it is regarded as a “functional” stimulant. Some argue that it may be useful for studying, writing papers, and so on. It also appears to enhance abstract and creative tasks and listening to music.

Motivation does not appear to be generated by this molecule. However, empathy, affection for others, social engagement, and emotional positivity are promoted. This may be, in part, due to the mood lift and euphoria it causes.

Aftereffects

As with other stimulants, there is a sense of “comedown” when the effects of 4F-EPH wear off due to the lower levels of neurotransmitter activity. Typical “comedown” effects experienced with stimulants include anxiety, cognitive fatigue, depression, irritability, motivation suppression, thought deceleration, and wakefulness (5). An additional effect noted by several 4F-EPH users was paranoia; one individual stated it lasted one hour.

First-hand or anecdotal reports can be further examined for information regarding routes of administration and dosages, onset and duration of effects, redosing, desired psychoactive effects, acute physical effects, other side effects, and coingested substances. These are examined in the following subsections.

Routes of Administration, Dosage, and Duration of Effects

According to user reports, 4F-EPH is typically taken orally (swallowed) or insufflated (snorted/sniffed). Other routes of administration include rectal (“plugging”), intravenous injection, vaping, sublingual, and rubbing on gums. Some (would be) users have asked their peers for advice about taking the molecule in other ways, for example, vaping in an e-cigarette; suggestions made include “parachuting” (wrapping in a cigarette paper and swallowing); “oral in a Pg (propylene glycol) solution”; “Get a 0.001 mg scale and gel cap your doses. Either you can take them as pills or open the capsule again later and snort straight from the capsule…”; “make a g-damn nasal spray with a water solution.”

Oral dosages are given at the following levels: threshold < 5 mg; light 5 to 10 mg; common 10 to 30 mg; strong 15 to 50+ mg; and heavy > 30 mg. Some cite a dosage of 65 mg over four hours. Nasal dosages are typically described as “bumps,” starting with 2.5 mg up each nostril and building up to 25 mg. A “large bump” is described as 30 mg.

The onset of effects when taken orally takes between 10 and 25 minutes; nasal administration can lead to effects being experienced within 3 minutes. The effects are reported to last four to six hours, with a peak around two to three hours. Residual or aftereffects can last from 1 to 12 hours.

Toxicity and Harm Potential

As there has been no scientific study of the long-term health effects or toxicity of 4F-EPH, combined with only a probably very limited consumption by humans, it is not possible to state what these might be.

Tolerance and Addiction Potential

Users report the development of tolerance to 4F-EPH being more rapid than with ethylphenidate and methylphenidate. They report a need to redose (even at low doses) or the use of higher doses to attain the same level of experience as with their first experimentation with 4F-EPH. Such measures result in feeling jittery, paranoid, and uneasy. One user claims it is “extremely dangerously addictive.” PsychonautWiki (2020) suggests that this molecule produces cross-tolerance with other dopaminergic stimulants.

Dangerous Interactions

There is little or no information specifically mentioned with regard to interactions between 4F-EPH and other substances. One Reddit contributor notes that taking a combination of 150 mg of 4F-EPH with 300 mg of magnesium citrate leads to “mania.” The general advice offered is to start with small doses and increment slowly.

Circumstances of Death

The deceased had a history of substance misuse. He had consumed a number of (unspecified) legal and illegal substances in the days prior to his death. These substances had a detrimental effect on his health and well-being. On July 11, he left [home?] under the influence of these substances. As a consequence of his behavior, members of the public contacted the police to report his actions, that is, causing a disturbance in a town center.

At about 16:45 that day police attended the locus where he had been detained by members of the public and arrested him. He was not charged with any offence. He was taken to a police station where he was assessed as unsuitable for detention in a police station.

He had reportedly been aggressive and kicking. The pathologist considered that such a situation suggested elements of stress that could well be associated with various physiological processes, generally causing further stimulatory effects, thus potentially increasing the risk of complications such as increased temperature and cardiac dysrhythmias. Elements of “excited delirium” could be present albeit this is a clinical diagnosis, which was not documented in the information available to the pathologist. In addition, the position of the decedent in the police vehicle prior to his collapse was not clear, albeit it would appear that he was likely sitting down while awaiting his turn to be triaged in the hospital. Although a sitting position would not be generally associated with significant impairment of his lung functions, it could arguably, depending on his body habitus, cause at least some degree of restriction of his breathing abilities that could in part impact on his risks of fatal complications. Taking all this into consideration along with the history and findings at autopsy and in view of the mechanisms of death noted above, there appeared to be no sufficient pathological evidence to implement with certainty the role, if any, of the restraint and body position in his death, although this could not be fully ruled out.

He collapsed and was, therefore, taken to a hospital in the same town and became unresponsive. He exhibited hypothermia, rhabdomyolysis, hepatic, and renal failure. Life was pronounced extinct, in the Intensive Treatment/Care Unit, at 17:25 on July 15 (three days after admission).

An inquiry was conducted into his death by the Police Investigations and Review Commissioner (PIRC) on behalf of the Crown, but no charges were brought against any individual (32). A FOI request was made by the lead author (JC) to PIRC, but no further information about events leading up the decedent’s arrest and detention was released (personal communication to lead author by PIRC, April 29, 2021).

Autopsy Investigations

An autopsy took place on July 20, 2016 (six days after death). The deceased was a White male aged 24 years. He was 1.90 m in height, weighed 103 kg, and had a body mass index of 28.5.

External findings of note were multiple red marks; hematoma; bruises on face, trunk, and upper and lower limbs. The deceased had areas of skin mottling and patchy hemorrhage, likely to be in part the result of his multiorgan failure and coagulopathy. There were, however, localized blunt-force injuries identified in particular on the forearms and the lower legs that were further explored and were found to be associated with underlying soft tissue injury. These would correlate with, but were not associated with, any significant damage or injury to structures or organs that would have directly caused or led to his death. A number of other blunt-force injuries including bruising and abrasions were noted on the body that could have occurred as a result of various mechanisms such as falls, impact with blunt objects or surfaces or other also potentially in part occurring during the restraint procedure. The deceased was reportedly handling a knife at various points. There were no findings at autopsy to suggest that sharp force injury has played a role in his death.

There was evidence of liver failure as well as kidney damage associated with collections of breakdown products of his skeletal muscles as noted clinically. Moderate autolysis of liver with evidence of prominent zone 3 necrosis with a background of mild to moderate preexisting hepatic steatosis was found. The proximal jejunum and spleen were congested.

The postmortem and histology results revealed congested lungs with localized marked edema. Histology also demonstrated patchy intra-alveolar hemorrhage and established bronchopneumonia; the latter was likely a terminal event.

The aorta showed mild atheroma. Neuropathology and extensive heart sampling showed no significant pathology. The latter would not preclude the possibility of a preexisting cardiac disease, albeit there were no suggestions on pathology grounds that this played a role in his death.

In view of the history of drug use over some time before the decedent’s collapse, it could be that the various terminally fatal mechanisms such as muscular, liver, and kidney insults could have arguably been initiated in the days or weeks prior to his hospital admission.

Toxicological Findings and Interpretation

Antemortem toxicology findings were: blood—alcohol 21 mg/dL, 4F-EPH 0.36 mg/L, MDMA < 0.4 mg/L, MDA < 0.4 mg/L; serum—4F-EPH 0.27 mg/L. Postmortem femoral blood, urine, and hair samples were taken for toxicology. These yielded the following results: blood—morphine 0.17mg/L, total morphine 0.21mg/L, 4F-EPH 0.078 mg/L, MDMA 0.15 mg/L, MDA < 0.1 mg/L, lignocaine 0.17 mg/L; urine—4F-EPH detected, morphine 0.36 mg/L. Unknown samples taken from the locus where he was arrested showed 4F-EPH in the form of white powder in a clear plastic packet and also in a clear plastic tub; two yellow amitriptyline tablets in a part blister pack; two plastic packets containing MDMA crystals; residue in five plastic packets contained combinations of MDMA, cocaine, and delta-9-THC; MDMA and delta-9-THC; and 4F-EPH, MDMA, and delta-9-THC.

Interpretation of toxicology results: The traces of alcohol in the hospital blood could well represent postmortem production, albeit this could reflect the use of alcohol particularly in view of the history provided. The postmortem morphine levels are consistent with its administration in hospital. The lignocaine level detected is consistent with use as a local anesthetic.

The most significant toxicological findings were the presence of MDMA, MDA, and 4F-EPH. MDMA and its metabolite MDA were noted at subfatal levels in the postmortem and antemortem hospital samples, albeit these were not possible to fully quantify in the hospital sample.

MDMA/ecstasy is thought to cause death through a number of mechanisms. These include the increased risk of hyperthermia/pyrexia and associated complications (such as organ failure and breakdown of skeletal muscle) as noted in the well-documented clinical history in this case. Other side effects such as neurotoxicity (including serotonin syndrome) and effects on the cardiovascular system have also been documented. Indeed, coadministration of two stimulants (i.e., amphetamine-type stimulants, such as MDMA or MDA, and/or cocaine) might increase both serotonergic and dopaminergic stimulation, through a synergic effect, so that serotonin syndrome is more likely to happen (33).

The antemortem and postmortem levels for 4F-EPH are the first recorded in the academic literature, or indeed reported anywhere, so cannot be interpreted by direct comparison with other cases; the toxicology laboratory, therefore, did not attempt to interpret them. As noted above, little is known about the effects of 4F-EPH.

On the other hand, ethylphenidate, the close analog of 4F-EPH, has been found to produce similar side effects to the amphetamines including the increased risk of pyrexia, tachycardia, paranoia, and tremor, which in turn would have complemented the effects of MDMA/MDA, thus potentially also playing a major role in this decedent’s fatality.

Cause of Death

Based on the evidence outlined above, the pathologist concluded that the cause of death “would appear to be the result of the complications of psychostimulant drug use in particular MDMA/MDA and potentially 4F-EPH with the possibility of concurrent ingestion of alcohol. These led to an increase in…body temperature associated with symptoms of paranoia and hallucinations and complicated by muscular breakdown, kidney and liver failure and pneumonia. The cause of death should therefore be…1a. Complications of MDMA/MDA and 4F-EPH toxicity.” Cause 2 was given as “drug abuse.”

This cause of death was formally handed down by a Fatal Accident Inquiry concluded on August 28, 2018. This was the wording subsequently recorded in the NRS database, where the event was coded and registered as an accidental drug poisoning.

Effects of MDMA

Acute consumption of ecstasy (MDMA, MDA) may give rise to a spectrum of physical complications including tachycardia, arrhythmias, asystole, hypertension, cerebral hemorrhage, thrombocytopenia, convulsions, coma, mydriasis, vomiting, diarrhea, metabolic acidosis, rhabdomyolysis, disseminated intravascular coagulation, and acute kidney failure. Increased core body temperature may be induced both by amphetamine-type stimulant consumption and by environmental factors. This can lead to excessive consumption of hypotonic fluids, which in turn can lead to hyponatremia (34).

It is also argued that acute ecstasy consumption leads to serotonin syndrome (35). This appears to be caused, in ecstasy users, by 5-HT1-like and 5-HT2 receptor stimulation induced by MDMA, leading to heightened central serotonin levels (36). Symptoms of this syndrome include mental confusion; agitation; hyperreflexia; incoordination; bruxism; trismus; enhanced physical activity; hypotension, hyperthermia; sweating; shivering; seizures, tremor, and nystagmus; rhabdomyolysis; metabolic acidosis; and myoclonus (34,37,38).

Serotonin syndrome is a possible factor in this combined MDMA/MDA and 4F-EPH-related death. Some of these symptoms are noted to have occurred in respect of the decedent. This suggests, therefore, that an increase in serotonin had occurred especially as no other drugs were detected that could have triggered such an event.

General noradrenergic/dopaminergic receptor stimulation may be responsible for symptoms such as hypertension, overarousal, and tachycardia (39). Concomitant administration of dopaminergic stimulants can enhance release of serotonin (40). More serious adverse consequences, such as delirium, seizures, and coma, are more likely to be experienced if MDMA is coingested with amphetamines and/or cocaine (41). Ecstasy-related deaths are more likely than amphetamine/methamphetamine-related deaths to have alcohol and cocaine detected than the latter, which are more likely to be found in combination with opiates/opioids (42).

Lethal blood levels of MDMA vary considerably where death is due to polydrug use: mean 2.90, median 0.76, range 0.04 to 41.5 mg/L. In fatalities where MDMA is associated with trauma, the average and range were somewhat lower: mean 0.862, median 0.483, range 0.035 to 4.81 mg/L. As might be expected, where MDMA is the sole drug implicated in death, these parameters are higher: mean 8.43, median 3.49, range 0.478 to 53.9 mg/L (43). The considerable overlap in the ranges of these concentrations indicates that as with other stimulants, an MDMA level on its own is insufficient to determine the cause of death. Drug use history, full circumstances of the death, and autopsy findings need to be considered (43).

The postmortem blood level of MDMA in the present case was 0.15 mg/L. This is toward the lower end of the ranges reported by Milroy for polydrug use and trauma deaths, but well below that seen for sole MDMA toxicity fatalities (43).

Effects of “Phenidate” Drugs

Generally, the stimulatory effects of 4F-EPH are considered to be weaker than those of ethylphenidate, although some users feel it is smoother. On the other hand, some individuals found themselves developing tolerance more quickly and having to redose or use higher doses to achieve the same effect.

At the time of writing, no poisonings or deaths, other than the case described here, involving 4F-EPH had been reported in the scientific literature, although Carlier et al. do refer to it (44). Indeed, this article is believed to be the first such article to describe a fatality in which the presence of 4F-EPH was recorded, let alone implicated. There is no relevant pharmacological information on this drug in terms of lethal dosage, LD₅₀, half-life, volume of distribution, and so on for either animal or human subjects. It is not possible to determine from a single blood sample either when a substance was consumed or the exact amount taken. Because of the lack of comparative data, it was neither possible to relate the 4F-EPH concentrations reported here to “recreational” or excessive use, nor to comment as to the toxicological significance of the concentrations. This article now provides some insights into the potentially fatal toxicity of 4F-EPH.

Methylphenidate Intoxications and Deaths

The undesirable effects of 4F-EPH appear similar to those produced by methylphenidate (MPH) (44,45). The main adverse effects in acute poisonings include: (1) central nervous system—anxiety, confusion, delirium, and hallucinations; (2) cardiovascular system—arrhythmia (atrial and ventricular), chest pains, hypertension, palpitations, and tachycardia—these may lead to coma, intracranial hemorrhage, and myocardial infarction/stroke; (3) effects on muscles—contraction, bruxism, and trismus; (4) fasciculation and rhabdomyolysis can lead to renal failure; and (5) hyperpyrexia (> 40 °C) leading to disseminated intravascular coagulation, sweating, and flushing. These groups of effects are commonly noted in poisonings involving amphetamine-type stimulants. Long-term use leads to the development of tolerance and the need to redose. Psychosis may also develop; symptoms typically include delusions, hallucinations, and paranoia. In turn, this may lead the chronic user to become anxious and suspicious generating aggression, hostility, and violent behavior. There are no user reports of 4F-MPH being used with MDMA.

Deaths involving methylphenidate have been ascribed to several mechanisms: intracranial hemorrhage, acute heart failure or arrhythmia, hyperpyrexia, rhabdomyolysis and consequent hyperkalemia or renal failure, and to violence related to its psychiatric effects (46). The ingestion of doses as low as 1.3 mg/kg has caused death (45). Methylphenidate blood levels >50 ng/mL are considered toxic (47,48). The first death involving the ingestion of methylphenidate reported central and peripheral blood levels of 980 and 1100 ng/mL, respectively (49).

Ethylphenidate Poisonings and Deaths

There are few academic papers dealing with poisonings and deaths involving ethylphenidate and analogs related to 4F-EPH; all of these relate to Europe. Three U.K. cases of acute ethylphenidate toxicity were reported by Bailey et al (50). Analytical confirmation was only available for one case, a 21-year-old male who had taken a cumulative total of 500 mg; the blood concentration 20 hours later was 0.24 mg/L. The authors highlighted the following symptoms similar to amphetamine-type stimulant use: agitation, bruxism, chest pain and palpitations, nasal irritation, and pain. Tachycardia was noted in two of these cases. Hypertension, dilated pupils, fever, anxiety, paranoia, and tremor were also noted.

The first death involving ethylphenidate was reported from Germany (51). However, the deceased had mitral valve endocarditis and pneumonia. The postmortem femoral ethylphenidate blood level of 0.1 mg/L may have been sufficient to affect the cardiovascular system.

Parks et al. documented 19 deaths in Scotland that occurred between July 2013 and December 2014 (52). Mean age at death was 37 (range 20-54) years; 14 cases were male; 16 cases came from Edinburgh and its environs. Average postmortem ethylphenidate femoral blood levels were: mean 0.39, median 0.25 (range 0.008-2+) mg/L. Other common substances identified were benzodiazepines (15), opiates (11), methadone (8), antidepressants (6), and antipsychotics (2). Drug toxicity was the sole or a potentially contributory factors in ten deaths, ethylphenidate being specifically cited in five cases. In no instance was ethylphenidate the sole drug detected.

Maskell et al. reported seven deaths from England that occurred between February 2013 and January 2015 where ethylphenidate was detected and quantitated (27). Four cases were ascribed to mixed drug toxicity and one to ethylphenidate toxicity; two were hangings. All decedents were male; median age was 25 (range 23-49) years. Opiates/opioids were present in three of the four mixed drug deaths. Other stimulants were present in three cases.

Ethylphenidate blood concentrations in the four mixed drug fatalities ranged from 0.03 to 0.14 mg/L; the two hanging cases have concentrations of 0.87 and 1.37 mg/L; the case involving only ethylphenidate had a concentration of 2.18 mg/L. When taken in the context of the overdose reported by Bailey et al (50), there may well be an overlap between “therapeutic”/“recreational” and toxic levels of ethylphenidate (27).

4-Fluoromethylphenidate Intoxications and Deaths

Papa et al. note that online user reports suggest that 4-fluoromethylphenidate (4F-MPH; 4F-TMP) is more potent than both methylphenidate and ethylphenidate but with less common adverse side effects such as anxiety, compulsive redosing, and muscle spasms. There are few documented cases of intoxications or deaths involving 4F-MPH (25).

The first intoxication involving 4F-MPH involved a female aged 26 years (25). She was admitted to an ED with the following symptoms: confabulation, confusion, crying, disorientation, incoherent speech, severe psychomotor agitation, palpitations, and tachycardia (100 bpm). With the addition of insomnia, these symptoms persisted for a week while she had been insufflating powder 4F-MPH acquired online. Normal admission vital signs included body temperature (36 °C) and blood pressure (120/75). Intravenous diazepam was given for sedation, with agitation subsiding within a day of admission; tachycardia persisted for two days. Discharge was allowed after two days with a prescription for quetiapine and promazine. Emergency department admission levels of 4F-MPH were: blood 32 ng/mL, urine 827 ng/mL.

4F-MPH was detected in the blood of three individuals intoxicated with NPS tested between 2015 and 2018 in a Polish department of clinical and forensic toxicology (53). One occurred in 2016 and two in 2018. Unfortunately, no further details are provided. A case report from another Polish institution indicates the probable consumption of 4F-MPH by a 28-year-old male with a ten-year history of drug abuse (54). According to his parents, he admitted the use of several drugs before losing consciousness and collapsing on the floor. On the way to hospital, his condition worsened with progressive respiratory failure and vomiting. On arrival, he was unconscious and had to be mechanically ventilated for three days. Tachycardia (120 bpm) was present; blood pressure was within the normal range (120/80). Aspiration pneumonia was diagnosed, along with mild acidosis, anemia, rhabdomyolysis, leukocytosis, high levels of C-reactive protein, and creatine kinase; in time, these all improved. During his first day in hospital, the patient was “partially disoriented, had formal thought disorders, inappropriate affect and cenesthetic hallucinations.” The emergency responders found a few pouches with tablets and herbs at the scene; these had labels like “4F-MPH,” “Bromazepam,” “Flunitrazolam,” and “mild cuddler” (probably synthetic cannabinoids). Toxicological examination of the male’s blood revealed traces of methylphenidate and methamphetamine; blood serum was positive for benzodiazepines (140.5 ng/mL). His pneumonia was successfully treated with antibiotics, and he received tranquilizers for his psychiatric issues. He was discharged after ten days, with further ambulatory therapy.

The only death involving 4F-MPH is reported by Shoff et al (26). They report that although this molecule had first been detected in their area in drug paraphernalia, the first death involving it occurred in 2018. A White male aged 25 years was experiencing paranoia, hearing voices, and seeing imaginary people. When his mother went to check on him the next morning, she found him unresponsive in bed; he was pronounced dead at the scene. No drugs paraphernalia were found, although the decedent was a known methamphetamine user. Key features noted at autopsy were edematous lungs, swollen brain, and distended bladder. Postmortem urine was positive for amphetamine and methamphetamine; cannabinoids; morphine, monoacetylmorphine (6-MAM), codeine, norcodeine; naproxen; diphenhydramine; and 3-methoxyphencyclidine (3-MeO-PCP). Gastric contents were positive for amphetamine and methamphetamine; 6-MAM, codeine, acetylcodeine; naproxen; diphenhydramine; and threo-4F-MPH (0.795 mg). Femoral blood was positive for amphetamine (0.135 mg/L) and methamphetamine (0.850 mg/L); morphine (0.268 mg/L), codeine (0.022 mg/L), papaverine, 6-MAM (1.835 ng/mL); diphenhydramine; 3-MeO-PCP; and threo-4F-MPH (0.012-0.049 mg/L). It is likely that the decedent suffered an acute heroin overdose. However, the effects of codeine, methamphetamine, 3-MeO-PCP, and 4F-MPH may have contributed to the death.

Comparison of Effects of 4F-EPH With Selected Amphetamine-Type Stimulants

Based on the user reports presented above, 4F-EPH has effects which are like those experienced by users of methylphenidate, ethylphenidate, 4-fluoromethylphenidate, as well as MDMA.

Treatment of individuals presenting to EDs who believe they have or are known to have consumed 4F-EPH should be in line with standard practice/protocols for dealing with amphetamine-type stimulants.

Comparative Toxicity of 4F-EPH

The blood level of 4F-EPH in the death described here was 4F-EPH 0.078 mg/L. This compares with methylphenidate blood levels >0.050 mg/L being considered toxic, and levels of central and peripheral blood levels of 0.980 and 1.100 mg/L reported by Cantrell et al (49). The present case is higher than the toxic level for methylphenidate but lower than lethal levels.

Lethal ethylphenidate (EPH) blood levels have been reported as follows: 0.1 mg/L (51); mean 0.39, median 0.25 (range 0.008-2+) mg/L (52); mixed drug fatalities 0.03 to 0.14 mg/L; hangings 0.87 and 1.37 mg/L; ethylphenidate alone 2.18 mg/L (27). The present case is within the levels for mixed drug fatalities involving ethylphenidate.

4-Fluoromethylphenidate (4F-MPH) levels of 0.012 to 0.049 mg/L in mixed drug toxicity deaths were reported by Shoff et al (26). The present case is higher than the 4F-MPH levels.

Given that the MDMA blood level in this case was comparatively low (0.15 mg/L), it is safe to conclude that 4F-EPH did contribute to this death. Moreover, there was no natural disease present to cause or contribute to the death.

Information Needs

Even with 27 documented cases of ethylphenidate-related deaths outlined above, more information is needed about its pharmacology and toxicology (27). How much more so for its analogs such as 4-MPH and 4F-EPH!

Fully appreciating the toxicological ramifications of a single novel NPS is problematic but the potential contribution of such molecules to fatalities cannot be overlooked (26).

Since analogs of methylphenidate are not included in regular screens for drugs of abuse, the number of intoxications, poisoning, and deaths involving such molecules is likely to be underestimated (25). It is important that ED staff and forensic toxicologists do not overlook the possibility of the ingestion of ethylphenidate analogs. Reference standards are available for many of these, including 4F-EPH, facilitating quick identification.

It is essential that, wherever feasible, full and detailed information regarding the circumstances leading to hospitalization or death is gathered. This will enable appropriate toxicological investigations and, if necessary, medical interventions to be undertaken.

Strengths and Limitations of This Study

This article has reviewed the scanty information available from online user reports about the experiences of those consuming 4F-EPH and the effects it engenders. Together with the detailed presentation of a case report of the first death involving this molecule, our research puts into the public domain the best information available at present. It can provide a basis for future in vivo, in vitro, and in silico research on the abuse potential, pharmacology, toxicity, and so on of a little known and understood NPS.

Due to legal restrictions in this case, only limited information is available on the circumstances of the decedent’s behavior leading up to his detention and subsequent events leading up to his death. A more detailed account of this period could provide insight into his behavior and whether it demonstrated the effects of drug consumption.