Novel psychoactive substances: overdose of 3-fluorophenmetrazine (3-FPM) and etizolam in a 33-year-old man

Abstract

Though illegal in the UK, in many countries novel psychoactive substances are quasi-legal synthetic compounds that are widely available online under the guise of research chemicals. These substances are relatively cheap and are often undetectable in standard drug screens. Nearly 200 such compounds are introduced yearly, and little is usually known about their metabolism or physiological effects. Consequently, managing patients in overdose situations on largely unknown substances usually involves supportive care, however anticipating and managing atypical side effects are challenging in the absence of knowledge of these compounds. In this report, we discuss our encounter with a 33-year-old unconscious man presenting with coingestion of a novel stimulant 3-fluorophenmetrazine with a rarely used benzodiazepine etizolam. This patient developed seizure-like activity and delayed widespread T-wave inversions, both of which ultimately resolved without sequelae.

Background

‘Legal highs’ or ‘new/novel psychoactive substances’ sold as research chemicals have a grey legal status in most countries, particularly in North America. Disguised with the label ‘Not for human consumption’, they are able to evade the regulatory processes in most countries.¹ These synthetic compounds have increasing popularity due to their accessibility, low cost, psychoactive effects and inability to be detected by screening drug tests like immunoassays (table 1).^{1 2} Up to 200 of these substances are designed every year, with the majority first making appearances in Europe.³ Given attempts by chemists to circumvent drug enforcement laws through slight alteration of parent compounds which are already illegal, in 2016 the UK banned all novel psychoactive substances.⁴ Nevertheless worldwide, these drugs are easily obtainable over the internet and present significant challenges to patient management in emergency and critical care settings.⁵

Table 1.

Sample list of common new/novel psychoactive substances*²

Group	Common examples	General usage reactions
Aminoindanes	2-A1, 5-IAI, MDAI, MMAI.	Analogues of amphetamines with euphoric effects.
Amphetamine-type compounds	3-FPM, 2-FA, 2-FMA, 3-FA, 3-FEA, 4-FA, 4-FMA, BZP, ethylphenidate, MDAI, mephedrone, MPDV, NRG-1.	Primarily stimulants, with possible psychedelic effects through dopaminergic, serotonergic and adrenergic pathways.
Arylcyclohexylamines	2 F-K, 2’-Oxo-PCE (O-PCE), 3-MeO-PCE, 4-MeO-PCP, PCE, methoxetamine.	PCP-like drugs, with dissociation, anaesthesia and hallucinogenic effects primarily through N-methyl-D-aspartate receptor antagonism.
Benzodiazepine/sedative-type compounds	Diclazepam, etizolam, flubromazepam, nifoxipam, pyrazolam.	Sedative, hypnotic, anxiolytic, anticonvulsant and muscle relaxant properties through enhancement of gamma-aminobutyric acid signalling.
Cannabinoids (synthetic)	APICA, BB-22, JWH-018, STS-135. THJ-018, THJ-2201 (may be sold as any of these names: Clockwork Orange, Black Mamba, Spice, Exodus Damnation, K2, Kronic, Northern Lights, Kaos).	Analogues of tetrahydrocannabinol, act on cannabinoid receptors.
Cathinone-like compounds	Alpha-PVP (Flakka), mephedrone (4-MMC, Meow Meow, M-CAT), methylone (bk-MDMA), MDPV (Ivory Wave), NRG-1 (Naphyrone).	Monoamine alkaloids with stimulant properties.
Phenethylamines	25i-NBOMe, 5-APB, benzodifurans (Bromo-Dragonfly), PMMA.	Psychedelic effects via serotonergic agonism.
Synthetic opioids/fentanyl analogues	Carfentanil, cyclopropyl fentanyl, furanylfentanyl, methoxyacetylfentanyl, U-47700.	Activates µ-opioid receptors, strong euphoria effects, high risk of respiratory depression.
Tryptamines	4-AcO-DMT, 4-AcO-Met, AMT, DMT, 5-Meo-DMT, 5-Meo-DPT.	Psychedelic and entheogenic effects, largely acting on serotonergic receptors.

*This list is only a representation of common new/novel psychoactive substances. The names listed are presented as they are commonly sold online.

3-FPM, 3-fluorophenmetrazine; PCE, eticyclidine; PCP, phencyclidine.

Typically, most patients who overdose on these substances appear in the emergency room either obtunded or unconscious. The approach to any unconscious patient must first involve immediate stabilisation, and once addressed, consider lethal and easily reversible causes that could kill the patient in the next few minutes, such as hypoglycaemia, overdoses and intracranial herniation. The patient’s history, usually from paramedics, along with a thorough primary survey and a few ancillary laboratory tests, should rule out most immediately life-threatening differential diagnoses and help initiate definitive treatment. In our patient described below, after definitive management of his airway and finding no other immediate concerns from the primary survey, the history from the paramedics of finding the 3-fluorophenmetrazine (3-FPM) and etizolam drug packages supported drug overdose as the cause of the patient’s symptoms. This case of drug overdosing on novel, cheap and easily obtainable psychoactive substances is unfortunately an increasingly common emergency room presentation. Patients should be reassessed frequently and intensive care expert opinion should be sought early. If novel substances are identified on history, a literature search for case reports may help identify uncommon side effects for which early detection could significantly improve patient outcomes.

Case presentation

A 33-year-old unresponsive man presented to the emergency department after being found by family members 1 hour post yelling and thrashing in his bedroom. Paramedics found two empty packages on the floor near the patient labelled ‘etizolam 50 mg’ and ‘3-FPM 500 mg’. Both labels stated ‘Not for human consumption’. On examination, he was responsive only to painful stimuli (Glasgow Coma Scale (GCS)=6, E1M4V1), with vitals respiratory rate 10/min, temperature 36.6°C, SpO₂88%, pulse 64 beats/min, blood pressure 104/61 mm Hg and blood glucose 5.1 mmol/L. Pupils were 5 mm bilateral and non-reactive. His airway was clear with equal air entry and regular palpable pulses. Oxygenation improved with a non-rebreather mask at 12 L/min oxygen. Initial ECG showed sinus rhythm. On emergency room arrival, he remained stable but still unresponsive. Arterial blood gas revealed respiratory acidosis (pH 7.21 and PCO₂76.5 mm Hg). Naloxone 2 mg intravenously was administered with no effect. The patient was subsequently intubated with ketamine and succinylcholine. A nasogastric tube was inserted, an arterial line was established, and a propofol infusion was started. Portable chest X-rays and CT head revealed no acute abnormalities. Blood alcohol was negative. A rapid 7-drug urine drug screen was positive for benzodiazepines and indeterminate for amphetamines. A more extensive 42-drug urine screen was negative for other commonly abused drugs.

On collateral history, this patient had no significant medical or surgical history other than anxiety treated with occasional lorazepam, however his prescription had run out 2 weeks prior. His known drug use history included distant cannabis use. Physical examination was significant only for abrasions on the scalp and lower limbs with no evidence of intravenous drug use.

Treatment

After workup in the emergency department, the patient was admitted to intensive care for monitoring. Abnormal four-limb movements concerning for possible seizure activity were observed in the afternoon of his first day in the hospital despite propofol infusion. This settled with lorazepam. He developed a fever of 38.9°C that same evening and was pan-cultured and started on vancomycin and metronidazole. An extensive workup revealed only positive sputum culture for Staphylococcus aureus, and his antibiotics were stepped down to cefazolin on the fourth day postadmission. By this time, no further abnormal movements were observed, and his propofol infusion was weaned, and he was extubated once awake.

Outcome and follow-up

On awakening, the patient endorsed oral use of 3-FPM and etizolam before losing consciousness. He also admitted to chronic use of 4-AcO-Met (azomet, metacetin) though he denied using any for several days. All these substances were purchased online. He denied suicidal intention and instead mixed up 3-FPM for etizolam as they came in identical bags and he inadvertently took a much higher dose of etizolam than intended.

On the fifth day after admission, he was transferred to a regular hospital bed from the intensive care unit but was noted to have new widespread T-wave inversions on ECG (figure 1). He was however asymptomatic. These improved prior to discharge on day 7 after having been cleared by psychiatry. Arrangements were made to follow up with his family doctor and for addictions counselling, but he declined both. Follow-up cardiac stress testing 5 days after discharge was within normal limits.

Figure 1.

ECG showing widespread T-wave inversions 5 days after admission.

Discussion

3-FPM, also known as PAL-593, first became available in 2014, and is a fluorinated version of phenmetrazine (figure 2A), an abused drug from the 1960s used as an appetite suppressant.⁶ 3-FPM acts as a norepinephine dopamine releasing agent and hence has stimulatory properties. To date, there are three case reports on 3-FPM misuse. The first is an observational case series from Sweden with 19 patients with analytically confirmed acute polyintoxication including 3-FPM.³ Unfortunately, no unique toxidrome was confirmed. Symptoms observed included tachycardia, reduced level of consciousness, agitation, delirium, dilated pupils, seizures, hypertension, respiratory depression and rhabdomyolysis.³ Another report from the UK involved a patient who used 3-FPM intravenously and required a period of renal replacement therapy and bilateral lower limb amputation following development of irreversible four-limb ischaemia.⁴ 3-FPM, in combination with the synthetic opioid U-47700 and several designer benzodiazepines, was found in the blood and urine of a 34-year-old man at autopsy.⁷

Figure 2.

Structures of drugs in this case report and closely related analogues. (A) 3-FPM (top) and its parent compound phenmetrazine (bottom). (B) Etizolam (top) compared with lorazepam (bottom). (C) 4-Aco-Met (top) and its parent compound psilocin (bottom). Images adapted with courtesy of Wikimedia Commons (public domain). Cl, chloride; F, fluoride; H, hydrogen; N, nitrogen; O, oxygen; S, sulphur.

Etizolam, a structural relative of benzodiazepines with the full range of benzodiazepine effects including anxiolytic and sedative properties, appeared online in 2011 (figure 2B). Medically, it is used in Japan where it was introduced in 1983 under the trade name Depas for anxiety and its muscle relaxant properties, with a half-life of approximately 6 hours.⁸ While etizolam is reversible with flumazenil in the overdose setting,⁹ rapid discontinuation can lead to benzodiazepine withdrawal syndrome (BWS) which can include hallucinations, psychosis and seizures. An exceedingly rare complication of BWS, neuroleptic malignant syndrome, has been reported in Japan in a patient with Parkinson’s disease and hypothyroidism after discontinuation of etizolam.¹⁰

4-AcO-Met, also known as 4-Acetoxy-MET (4-Acetoxy-N-methyl-Nethyltryptamine), azomet or metacetin, is a novel synthetic hallucinogenic tryptamine very similar in structure to psilocin, a classical psychedelic substance with euphoric properties (figure 2C).² At present, there is no scientific literature about the side effects of this compound which first appeared in 2014.

In all cases of drug overdose, regardless of the primary compounds involved, it is important to keep in mind that most presentations will involve polyintoxication, either because the patient is likely taking multiple substances or the substance used has been cut with other illicit substances unknown to the user. Consequently, given the abundances of opioid abuse, naloxone administration should strongly be considered, especially in circumstances of unstable vitals even if an opioid toxidrome is not readily apparent.¹¹ While a rapid urine drug screen might be a useful adjunct in determining drug classes of concern, no drug screen is likely to aid in the management of patient stabilisation. As previously mentioned, most novel psychoactive substances cannot be detected in routine screens, and confirmatory testing is rarely available in most centres and not likely to be clinically useful. Hence, managing drug overdoses relies critically on supportive measurements. In the case of our patient with the overdose of the benzodiazepine etizolam, one could consider using flumazenil, however, as previously discussed, this carries the risk of BWS particularly concerning for seizure-like activity.¹¹ Further, in a patient treated with flumazenil with cointoxication of other substances, the benzodiazepine may be antagonising stimulatory or proconvulsant properties of these substances.¹¹ Novel psychoactive substances with stimulant properties are often abused with benzodiazepine-class drugs to alleviate undesired side effects such as tachycardia and tremors.⁷ In our patient, the seizure-like activity noted early in his treatment course could have been either from the stimulant 3-FPM or from withdrawal of etizolam. Either way, his symptoms were well managed with lorazepam. Finally, once an overdose patient is beyond the critical care setting, it is still imperative to frequently examine the patient with appropriate investigations for delayed signs of organ damage. Interestingly, our detection of late-onset widespread T-wave inversions did not appear to have any significant clinical significance given their complete resolution within 1 week.

Once an overdose patient is stabilised, the clinician should investigate the aetiology of the overdose, especially examination for suicidality, with consultation to mental health and psychiatric services as appropriate. Resources for addictions counselling should be made available, and the patient encouraged to follow up with a family physician for monitoring of both long-term sequelae and treatment progress.

Learning points.

• The use of designer novel psychoactive substances is rapidly increasing but their side effects in overdoses are largely unknown.

• Polyintoxication should be considered in every patient presenting with an overdose.

• In any unconscious patient with a suspected drug overdose, other aetiologies for the patient’s presentation must also be considered.

• The care of patients with novel substance overdose largely involves supportive measures, and close observation is vital to facilitate early detection and prompt management of evolving symptoms.