#66913: Novel Psychoactive Substances: Emerging Drugs of Abuse

A predictable pattern, termed a drug epidemic cycle, has long been observed with some recreational drugs. The cycle begins when the drug first becomes used by a narrow population segment, followed by dramatic increases in its use, possibly fueled by accounts of highly desired effect, perceived safety, or legality. With widespread use come initial reports of addiction or adverse effects from its use, followed by medical and public health alarm, extensive and sometimes sensationalized media reporting, rushed legislation criminalizing its use or possession, and then declining prevalence of its use [17]. This pattern has been shown in the United States using poison control center data to obtain valuable information on population-level trends in the abuse of specific and class-wide substances. According to the American Association of Poison Control Centers, use of synthetic cathinones resulting in toxic effects peaked in 2012 and cannabimimetics reached highest rates in 2015, indicating the turning point in the epidemic cycles [36].

NPS epidemic cycles also depend on sub-groups of people, for example music and club subcultures. It has been shown that music and club cultures and recreational drug preferences have evolved in tandem. Cocaine was favored in the 1970s and 1980s disco scene. Underground raves started appearing in the late 1980s and early 1990s, and MDMA (sold and referred to as Ecstasy) was the favored psychoactive at these events. MDMA remained favored by participants in the domestic rave, club, and warehouse party scenes during the 1990s to early 2000s, along with gamma-hydroxybutyrate (GHB) and ketamine. Other growing scenes were gay nightclubs and circuit parties, with methamphetamine the preferred circuit party drug. Efforts to improve safety through harm-reduction approaches (e.g., testing pills, information dissemination) developed during this period [25].

In the 2000s, electronic dance music grew out of rave culture, with indoor club or warehouse productions and outdoor festivals. Outdoor electronic dance music events are often large, with tens of thousands of participants and corporate sponsorships. These events have been plagued by NPS-related emergency department admissions and fatalities among participants. Independent harm-reduction groups began offering free drug sample testing to inform participants about the true contents of what was sold to them as MDMA or LSD. However, event promoters and venue owners have banned drug testing groups from admission, concerned that allowing their entrance would appear to condone drug use. This stance is a consequence of the 2003 Reducing Americans' Vulnerability to Ecstasy (RAVE) Act, which holds promoters legally responsible for drug dealing at their events. Some law enforcement members began misinterpreting the harm-reduction services and conflating them with drug promotion [42].

In addition, proliferation of NPS is often seen in persons attempting to avoid drug-testing detection due to probation/parole, seeking employment, residing in a sober facility, or joining the military. Most report using cannabimimetics as a cannabis substitute during drug-testing periods and resuming cannabis when drug testing has ended. In one study, nearly all learned of SCRA from someone using the substances to avoid drug-testing detection.

Schedule I is the most restrictive category under the Controlled Substances Act (CSA) and is reserved for drugs with no recognized medical use and a high abuse liability (e.g., heroin, LSD). The DEA has placed numerous NPS into Schedule I. This is an ongoing process, and information about scheduling and a link to the most recent list of Scheduled drugs is found on the DEA website at https://www.dea.gov/drug-information/drug-scheduling [9]. In addition, the Commission on Narcotic Drugs maintains international scheduling decisions, available on the UNODC website at https://www.unodc.org/unodc/en/commissions/CND/Mandate_Functions/Scheduling.html.

Other attempts at regulating NPS are still being developed. The UK responded to emerging NPS by enacting the European Psychoactive Substances Act of 2016, a generic drug legislation pre-emptively banning entire groups of drugs, making it illegal to produce or supply. The goals of the Act were to end NPS sales; end the issue of NPS emerging faster than the government could ban them; reduce NPS use; and reduce NPS-related harm. However, studies have found that there was an opposite effect, and the legislation resulted in manufacturers, dealers, and users shifting to street markets and dark web sales [13]. In the United States, House Bill 1732: Synthetic Drug Control Act of 2017 was introduced to amend the Controlled Substances Act to include several NPS as Schedule I drugs; the HB was not passed. In 2019, the Stop Importation and Manufacturing of Synthetic Analogues (SIMSA) Act was introduced, but no action was taken. This Act has been reintroduced several times, but as of December 2024 has not been passed [22]. Many individual states have enacted legislation to regulate the distribution and use of NPS [2].

For decades, the NPS market has been dominated by SCRA and synthetic cathinones. However, in the 2010s, opioid receptor agonists, namely fentanyl, have become the deadliest drug threat in the history of the United States [6]. Acetyl fentanyl, with one-third the potency of fentanyl, appeared sporadically in the United States during 2014 and 2015 and resulted in at least 60 fatalities, a probable underestimate, suggesting, and correctly predicting, a fentanyl analog resurgence that began during the opioid crisis [6]. The DEA identified 15 novel fentanyl analogs during 2013–2014; in 2017, they identified 2,825 new fentanyl analogs, marking an increase of nearly 19,000% in less than five years. In 2020, the DEA's National Drug Threat Assessment reported nearly 88% of NPS tested was comprised of opioids, most commonly fentanyl (90% of all opioids), compared with 5.3% benzodiazepines, 3.6% cathinones, and 2.4% cannabimimetics identified. In addition, a high proportion (53%) of samples purchased as fentanyl contained only fentanyl and no other substance, and 31% of fentanyl identifications contained fentanyl and heroin [6,38].

With potency roughly 100 times greater than morphine and 30 to 50 times greater than heroin, as little as 0.25 mg of fentanyl can be fatal. In addition, there is significant risk that illicit drugs of any type have been intentionally contaminated with fentanyl. Because of its potency, low cost, and ease of access, drug dealers and manufacturers have been found to switch out or mix fentanyl with other drugs, including heroin, methamphetamine, and cocaine, increasing the likelihood of a fatal interaction. Fentanyl is also being falsely sold as a variety of different pharmaceutical drugs and is often manufactured to look like a prescription tablet. In 2023, the DEA seized more than 80 million fentanyl-laced fake pills and nearly 12,000 pounds of fentanyl powder, the equivalent to more than 390 million lethal doses of fentanyl [35].

As a direct consequence of the market becoming dominated by highly potent opioid NPS, especially fentanyl, the rate of overdose deaths has increased remarkably. The monthly rate of all drug overdose deaths in January 2015 (the first year of NPS reporting) was approximately 48,000; among these, 5,800 deaths (12%) were attributed directly to synthetic opioids. Overall, overdose death rates continued to climb before peaking at 113,000 in August 2023, of which 79,000 deaths (70%) were attributed to synthetic opioids. A decrease of 15% in all overdose death rates and 18% in synthetic opioid death rates was noted in June 2024 [23].

Despite the decline in synthetic opioid deaths, the DEA warned in the 2024 National Drug Threat Assessment report that fentanyl is still a major issue and is being further complicated by the nitazenes NPS class. Nitazenes are synthetic opioids, like fentanyl, but some nitazenes can match or surpass the potency of already deadly fentanyl. Nitazenes first began appearing in fentanyl mixtures in the United States in 2019. When combined with fentanyl, the effects of both drugs are heightened, which significantly increases the chance of fatal drug poisoning. In 2023, four novel nitazene drugs were identified [6].

Xylazine is a sedative used in veterinary practice and has historically been thought to be associated with a low risk of illicit use. However, in 2018, the emergency of xylazine combined with the opioid fentanyl produced was identified in the United States, a mixture known as "tranq" in illicit drug markets [6]. In 2023, fentanyl adulterated or associated with xylazine (FAAX) was identified as an emerging drug threat. In 2024, xylazine was found in 36% of fentanyl powder samples submitted to the DEA for testing, and nearly 6% of fentanyl pills were found to be adulterated with xylazine [6,16].

The growing issue of FAAX is of particular concern, as it complicates the reversal of opioid overdoses with naloxone and is responsible for widespread reports of injection site infections and necrosis resulting in amputations. Furthermore, people chronically exposed to FAAX often struggle with difficult withdrawal symptoms that may present unique treatment challenges compared to opioid withdrawal alone [16].

The Office of National Drug Control Policy released the Fentanyl Adulterated or Associated with Xylazine Response Plan outlining protocols to prevent xylazine-involved overdoses, ease withdrawal symptoms, and manage an effective treatment and recovery process for people with opioid use disorder who are chronically exposed to FAAX [16].

Medetomidine has also been flagged as potential emerging risk, with effects similar to xylazine, but more potent, with higher alpha2-adrenoceptor selectivity, greater lipophilicity, and faster elimination [16].

Amphetamine is a substituted phenethylamine, formed by adding an alpha-methyl group to yield alpha-methyl-phenylethylamine. Amphetamine is modified to produce substituted amphetamines. Methylation of the terminal amine forms methamphetamine. A methylenedioxy substitution on the phenyl ring forms MDMA. Adding a ketone oxygen group at the beta position of the side-chain forms cathinone, termed beta-keto-amphetamine. Amphetamine, cathinone, and MDMA are likewise parent structures of numerous stimulant and empathogenic (MDMA-like) NPS; cathinone is the parent of most "bath salts" NPS [1,8,10].

All phenethylamines produce their stimulant, entactogenic, and/or hallucinogenic effects by increasing synaptic monoamine levels. Dopamine, serotonin (5-hydroxytryptamine or 5-HT), and norepinephrine are the monoamine neurotransmitters. Normally, dopamine, serotonin, or norepinephrine is released into the synaptic cleft, and then cleared from the synapse through uptake by their respective transporter. The last step involves vesicular monoamine transporter-2 (VMAT-2) located on the vesicular membrane. VMAT-2 uptakes the monoamines retrieved from the synapse and packages and stores them in synaptic vesicles for later release [1,8,10].

Phenethylamines increase synaptic monoamine levels by acting as inhibitors (blockers) or substrate releasers. Blockers inhibit monoamine transporter (re)uptake by competing with monoamine for binding sites on reuptake transporters to reduce synaptic clearance. Releasers induce the release of newly synthesized monoamine pools and release monoamines from pre-synaptic vesicle stores. The drug molecule permeates the intracellular space to inhibit vesicular reuptake of monoamines within the cell, induce transporter-mediated sodium currents (i.e., depolarization), and initiate transporter-mediated monoamine efflux (i.e., reverse transport or release). Outflow of cytoplasmic monoamines into the synaptic cleft is increased [1,8,10].

The net result of increased synaptic monoamine concentration is greater activation of post-synaptic dopamine, norepinephrine, or serotonin receptors, which transmit the amplified electrochemical signaling downstream for relay through various pathways to produce clinical effects of the phenethylamine derivative. Phenethylamines differ by monoamines targeted, relative monoamine activating potencies, and mechanism of monoamine increase (i.e., blockers, releasers, or both). Differences in potency, duration of effect, desired and adverse effects, abuse potential, acute toxicity syndromes, and neurotoxicity potential result from these varied interactions with monoamine systems and from interaction with non-monoamine transmitter systems [1,8,10].

Substrate releaser-induced depolarization puts neurons at risk, as seen with methamphetamine-associated dopamine neuron dysfunction and serotonin neuronal depletion from the use of fenfluramines. Releasers also disrupt vesicular storage to induce monoamine release, potentially contributing to persistent functional deficit in monoamine neurons through neurotransmitter depletion and loss of functional transporters. These potential neurotoxic mechanisms are not found in inhibitors [1,8,10].

More than 120 years ago, cathinone, the parent compound of this drug class, was isolated from Catha edulis (khat), a plant cultivated and chewed as a recreational and stimulant drug in Africa and the Arabian Peninsula for centuries. Beginning with the synthesis of methcathinone in 1928 and mephedrone in 1929, many cathinone derivatives and analogs were synthesized and investigated or introduced into clinical use as anorectics, CNS stimulants, or antidepressants. Overall, problems with abuse and dependence have limited their clinical utility. Methcathinone was used in the former Soviet Union as an antidepressant in the 1930s and 1940s but was removed from clinical use due to problems with its abuse. It has been most widely used as a drug of abuse in countries formerly part of the Soviet Union. Another derivative, pyrovalerone, is a stimulant first synthesized in 1964. It was investigated for use in treating chronic fatigue, lethargy, and obesity but was withdrawn due to abuse and dependency in users. Methylone was created and patented by Jacob Peyton and Alexander Shulgin in 1996 as an antidepressant but never entered clinical use. MDPV was developed by Boehringer Ingelheim in 1969 and subsequently prescribed for chronic fatigue and lethargy before its abuse liability became apparent [1,57].

As of 2024, only two cathinones are in clinical use in the United States. Diethylpropion is used as an anorectic but is infrequently prescribed due to abuse and dependence liability and better available options. It has also shown neurotoxicity in preclinical studies. The most successful cathinone derivative is bupropion, a ring-substituted cathinone widely used in the United States and Europe as an antidepressant and smoking-cessation aid under the brand names Wellbutrin and Zyban. This drug has been shown to have liability for misuse and abuse when used in methods other than intended(crushing to ingest nasally or intravenously, or by smoking) creating a milder cocaine-like effect [58].

The first documented large-scale abuse of synthetic cathinones occurred with methcathinone in the former Soviet Union in the 1970s and 1980s. Clandestine methcathinone manufacture first appeared in the United States in Michigan in 1991, followed by significant problems with abuse in the early 1990s [58]. In Europe, novel cathinone compounds emerged later in the 1990s, immediately followed by the rising prominence of "bath salts," which began appearing in the United States in 2009 [1,57].

Cathinone and its derivatives are closely related to phenethylamine, MDMA, and the classic stimulants amphetamine and methamphetamine in use in various settings since the 1930s. Cathinone, amphetamine, and MDMA are parent molecules of all known synthetic cathinones on the NPS market sold through the Internet, retailers, or street dealers [1,8].

As discussed, adding an alpha-methyl group to phenethylamine forms amphetamine. Methylation of the terminal amine then forms methamphetamine and greater CNS potency. Some cathinones are beta-ketone analogs of amphetamines. The parent cathinone is formed by adding a ketone oxygen group at the beta-carbon position on the amino side-chain of amphetamine, making cathinone its beta-keto analog (or bk-amphetamine). A ketone group added to methamphetamine forms methcathinone and the N-methyl derivative of cathinone [1,58].

MDMA is formed by a methylenedioxy substitution on the phenyl ring of amphetamine. Other cathinones are formed from MDMA and derivatives by adding a ketone group; thus, MDMA forms methylone or bk-MDMA; methylenedioxyethylamphetamine (MDEA or "Eve") forms ethylone or bk-MDEA; and N-methyl-1,3-benzodioxolylbutanamine (MBDB) forms butylone or bk-MBDB [1,58].

The molecular structure of cathinone is modified to form new cathinones through N-alkylation, which is achieved by substitutions in the phenyl (aromatic) ring or at the alpha-carbon position. Cathinones without ring substitution produce mainly stimulant effects. Ring substitution with a secondary or cyclic amino group (usually alkyl, alkoxy, or methylenedioxy) confers varying degrees of entactogenic and other effects similar to MDMA. All cathinones, whether or not ring substituted, possess primary stimulant properties [17,58].

As with amphetamines and MDMA, the subjective and physiologic effects of cathinones result from increased synaptic concentrations of the monoamines dopamine, norepinephrine, and serotonin. In addition to those discussed for phenethylamines, cathinones inhibit monoamine oxidase (MAO), especially MAO-B, reducing the breakdown of dopamine and phenethylamine [8,58].

Several cathinones and amphetamine derivatives are grouped by mechanisms of action resembling classic stimulants, which can help in the understanding of their clinical effects. Cathinone derivatives have been categorized into four sub-families based on chemical structure, with novel drugs being created by slightly altering each structure [1,57]:

Similar to cocaine, cocaine-MDMA-mixed cathinones show a ratio of dopamine versus serotonin inhibition ranging from 1 to 5 (dopamine>serotonin). With methylone, ethylone, and butylone, their corresponding non-beta-keto analog entactogens MDMA, MDEA ("Eve"), and MBDB are 10-fold more selective for serotonin compared with dopamine. These cathinones are more dopaminergic in monoamine transporter inhibition activity than their serotonergic entactogen analogs. Overall, the cocaine-MDMA-mixed cathinones are comparable to MDMA in monoamine-releasing activity, although the overall pharmacologic effects of mephedrone and methylone share the dopamine system-stimulating properties of amphetamine and methamphetamine [1,58].

Mephedrone is equally potent at dopamine and serotonin inhibition. It is a more potent releaser of dopamine than MDMA and produces a rapid and pronounced increase in nucleus accumbens dopamine levels, similar to amphetamine and unlike MDMA. However, mephedrone produces strong increases in extracellular serotonin similar to MDMA and unlike amphetamine.

Methylone is a slightly more potent dopamine inhibitor than a serotonin inhibitor. It has been found to elevate extracellular monoamine levels in the nucleus accumbens, similar to MDMA. Ethylone is an equipotent dopamine, serotonin, and norepinephrine inhibitor and releases serotonin. Butylone also releases serotonin, but it is a slightly more potent dopamine than serotonin inhibitor.

Naphyrone shows a monoamine uptake transporter inhibition profile similar to cocaine, with equal potency at all three transporters and no monoamine releaser activity. Naphyrone is structurally related to pyrovalerone and its derivative MDPV, but it is functionally distinct due to its greater absolute and relative serotonin-inhibiting potency [43].

This group of NPS includes mephedrone, 4-ethylmethcathinone (4-EMC), 4-FMC, 4-bromomethcathinone (4-BMC or brephedrone), 4-FA, and 4-fluoromethamphetamine (4-FMA). Substances in this group are more serotonergic (i.e., have a lower dopamine/serotonin ratio) than their amphetamine, methamphetamine, and methcathinone analogs [58,44].

The 4-methyl, 4-ethyl, and 4-bromo groups show enhanced serotonergic properties versus the 4-fluoro group. The para-substituted amphetamines release norepinephrine and dopamine; 4-FA, 4-FMA, 4-MEC, and 4-EMC also release serotonin (similar to MDMA). Most para-substituted amphetamines show 5-HT2A receptor affinity, without relevant 5-HT2B receptor activation. The enhanced direct and indirect serotonergic agonist properties of para-substituted amphetamines/cathinones are associated with greater MDMA-like effects [58,44].

Cathinone and methcathinone show pharmacologic profiles highly similar to their non-beta-keto analogs amphetamine and methamphetamine, including their relative monoamine transporter inhibition profiles with high inhibitory potencies at dopamine and low potencies at serotonin. They are potent releasers of dopamine but not of serotonin [1,58].

Flephedrone inhibits dopamine but not serotonin, similar to its analog 4-FA. It has a dopamine/serotonin selectivity profile equal to the methamphetamine-like cathinones, but with higher 5-HT2A receptor binding and agonism, similar to mephedrone and MDMA [1,58].

Pyrovalerone and its derivative MDPV are very potent dopamine inhibitors—at least 10-fold more potent than cocaine and methamphetamine. They are weak serotonin inhibitors and thus show dopamine/serotonin inhibition ratios greater than 100. MDPV and pyrovalerone are also highly potent norepinephrine inhibitors. Pyrovalerone and MDPV do not produce dopamine efflux, and the activity of pyrovalerone-derivative cathinones is purely transporter uptake inhibition [58,44].

Bupropion is a ring-substituted cathinone and a dopamine and norepinephrine reuptake inhibitor. Its close structural and functional similarity with psychoactive cathinones suggests it may be beneficial in the treatment of cathinone addiction and craving. There is some evidence of benefit in treating selected methamphetamine-dependent patients with bupropion, although effectiveness has not been consistently shown [58].

PMA and PMMA are potent norepinephrine and serotonin transporter inhibitors and releasers and have been sold as MDMA. However, they are substantially more toxic. In 2014, PMA/PMMA sold as MDMA led to 29 deaths in the UK [1,14].

4-MTA, the methyl-thio analog of PMA, has dominant serotonergic action and a high risk of serotonin toxicity. Methedrone is the beta-keto analog of PMMA, and whether this cathinone carries the toxicity of its parent compound is not known [1,58,43].

Mephedrone

Mephedrone can produce the sought-after entactogenic effects of MDMA, particularly the feeling of enhanced emotional and physical connection to others. Other desired effects include intense stimulation, alertness, euphoria, sociability and talkativeness, moderate sexual arousal, perceptual distortions, and intensification of sensory experiences. The numerous unwanted effects are common to all cathinones and result from hyper-dopaminergic, hyper-adrenergic, and hyper-serotonergic output. The effects are often followed by intense compulsion to re-dose. Tolerance develops quickly, and brief drug effect and urge to re-dose can lead users to ingest successive doses, often in excess of 1 g [1,8,58].

Following single-dose mephedrone, brain dopamine peaks in 20 minutes and returns to baseline within two hours, 10 times faster than MDMA and two times faster than amphetamine. Dopamine levels increase 496% following a single dose of mephedrone, compared with 412% with amphetamine and 235% with MDMA. Serotonin levels increase by 941% with mephedrone, 165% with amphetamine, and 911% with MDMA. An intranasal dose of 25–75 mg or an oral dose of 150–250 mg can induce intense craving and compulsion to re-dose—stronger than that experienced with MDMA. Intranasal users rate mephedrone as more addictive than cocaine. Mephedrone alone is not neurotoxic to dopamine neuron terminals, but its co-administration with MDMA, amphetamine, and methamphetamine enhances neurotoxicity [1,8,58].

Methylone

Relative to MDMA, 100–200 mg oral methylone produces calm euphoria, alertness, restlessness, a strong feeling of empathy, and milder stimulation. Unlike methamphetamine, methylone is a weak motor stimulant, and unlike MDMA, methylone induces minimal hyperthermia and little long-term cortical or striatal amines alteration. It has shown antidepressant effects and demonstrates little long-term cortical or striatal amine alteration. The side effect profile primarily reflects sympathomimetic activity. Fatalities attributed to methylone often involve polysubstance use [1,8,58].

MDPV

Entering the domestic NPS market in late 2010, MDPV quickly rose in prominence and notoriety. Its pharmacologic actions closely resemble pyrovalerone and alpha-PVP. Rapid blood-brain barrier penetration confers high potency. Full effects peak at 90 minutes and last three hours. Relative to cocaine, MDPV shows 50-fold greater dopamine potency and 10-fold greater norepinephrine potency, predictive of pronounced sympathomimetic stimulation and euphoria.

MDPV imposes risks from the slim dose-response margin between desired (2–10 mg oral) and adverse (>10 mg oral) effects. Effects include physical and mental stimulation, increased sociability, euphoria, and potentially severe prolonged panic attacks, agitation, anhedonia, confusion, intense paranoia, and depression. An unpleasant comedown, significant craving, compulsion to re-dose, and rapid tolerance are often reported. Users have repeatedly re-dosed from intense craving and to counteract unpleasant comedown symptoms, increasing the risks of overdose and toxicity. More than other cathinones, MDPV is linked to excited delirium syndrome [1,8,58] .

4-MEC

4-MEC is a methcathinone derivative that produces stimulant, euphoric, and empathogenic effects. 4-MEC users frequently report multiple re-dosing and difficulty refraining from re-dosing if more 4-MEC is available. Tolerance quickly develops [1,8].

As noted, mephedrone can be nasally ingested (snorted), but most cathinones are orally ingested. They cannot be smoked because their free bases are highly labile. Mephedrone, MDPV, 4-MEC, and pentedrone are water soluble, allowing injection. Mephedrone has been injected with heroin to simulate IV heroin/cocaine effects ("speedball") [8,58]. Other ingestion approaches are "bombing," with mephedrone powder wrapped in cigarette paper and swallowed, and "keying," an approach to get a crude dose estimate by dipping a car or house key into powder and then ingesting nasally. It is thought the powder from five to eight "keys" amounts to 1 gram [1,8].

The side effect profile of cathinones reflects relative contribution from dopamine, serotonin, and/or norepinephrine activation. Sympathomimetic effects common to all cathinones include tachycardia, tremor, sweating, hypertension, mydriasis, or hyperthermia. Excessive dopamine release can induce psychosis and confusion, while excessive serotonin release can induce myoclonus, nausea and vomiting, and agitation. Additional possible side effects include seizures, bruxism, prolonged panic attacks, insomnia, headache, tinnitus, vertigo, muscle twitching, dizziness, altered vision, short-term memory problems, anhedonia, depression, and suicidal thoughts. Cathinones closely resemble amphetamines in molecular structure, but differ by greater potential for severe and protracted adverse effects, potentially even from a single dose [1,58].

Severe Adverse Effects and Excited Delirium Syndrome

Excited delirium syndrome is a life-threatening and potentially fatal state of agitated delirium and autonomic dysregulation. It is the most severe manifestation of toxicity/overdose with cathinones use. Cannabimimetics and other NPS can also induce excited delirium, but cathinones-induced excited delirium is the most documented in scientific literature and the lay media.

Cathinones-induced agitated delirium or psychosis may persist for weeks, even from a single dose. Close to 80% of patients presenting for emergency medical care following cathinone use exhibit agitation ranging from mild to severe psychosis requiring chemical and physical restraint. With severe agitation, the patient may require restraint and transport to a medical setting by law enforcement personnel. Agitation can be exacerbated by concurrent use of alcohol or other drugs, such as cocaine. Dramatic cases of disorganized and agitated behavior manifesting in severe aggression, violence, homicidal combative behavior, self-mutilation, or suicide have received media coverage due to injury and loss of life. Delusions of persecution and auditory hallucinations during binge use have been described in users with a negative history of psychosis [41].

The bizarre, aberrant behavior during cathinone-induced psychosis encountered by poison control and emergency medical experts led to their description as embodying the combined worst attributes of methamphetamine, cocaine, phencyclidine, LSD, and MDMA. In a case series, poison control experts in Kentucky and Louisiana described their encounters with individuals displaying "aggressive violent behavior, hallucinations, and paranoia in higher percentages than previously reported" following synthetic cathinone use [59]. Behavioral descriptions included those who were found "jumping out of a window to flee from non-existent pursuers; requiring electrical shock (Taser) and eight responders to initially subdue the patient; repeatedly firing guns out of the house windows at 'strangers' who were not there; walking into a river in January to look for a friend who was not there; leaving a 2-year-old daughter in the middle of a highway because she had demons; climbing into the attic of the home with a gun to kill demons that were hiding there; and breaking all the windows in a house and wandering barefoot through the broken glass" [59]. Also described was a patient fatality from a self-inflicted gunshot wound while delusional. Investigation into possible causality in each of these cases found that MDPV was present in every case and that MDPV was the sole cause of the behavioral toxicity [59].

MDPV has been the primary cathinone detected in patients hospitalized for synthetic cathinone toxicity and overdose in the United States and has become the cathinone most responsible for excited delirium. MDPV cross-reacts with the phencyclidine (PCP) immunoassay used in hospitals, suggesting some cases of severe neuropsychiatric toxicity following MDPV use may have been falsely attributed to PCP. In addition to paranoia, psychosis, and agitation associated with all cathinones, high-dose MDPV use can induce extreme anxiety and intense prolonged panic attacks, aggressive behavior, "superhuman" strength, combativeness, and potentially terrifying hallucinations [58,41].

The first case report of fatality following acute MDPV toxicity described a sequence beginning with arrival to the emergency department, where the patient went into cardiac arrest with pulseless electrical activity. Despite rapid aggressive intervention that restored spontaneous circulation, the patient subsequently developed coagulopathy, rhabdomyolysis, renal failure, hepatic failure, and anoxic brain injury and ultimately died [56].

Numerous cases of organ damage and other life-threatening sequelae have been documented following cathinone use, including acute tubular necrosis and renal failure resulting from severe renal tubular vasospasm and elevated creatine kinase [60]. Seizure activity or anion gap metabolic acidosis has resulted from excessive anaerobic metabolism induced by excessive systemic monoamine elevation. Several fatalities following mephedrone use were linked to severe hyponatremia and cerebral edema. MDPV exposure in one patient led to fulminant hepatic failure and disseminated intravascular coagulation. Most fatalities following cathinone use have resulted from aggression/self-harm in the context of severe agitation and psychosis [56,61].

The naphthoylindole sub-group of SCRA was independently synthesized by John W. Huffman (JWH-series) and Alexandros Makriyannis (AM-series) to identify the structural requirements for selective binding affinity to the CB1receptor. Despite a negligible selectivity for CB1, synthetic cannabinoids containing N-alkylated tail groups bearing four to six carbon atoms demonstrated effective hydrophobic interactions with the binding pocket of the receptor, leading to an increase in affinity, whereas shorter (or longer) N-alkyl groups decreased affinity significantly [1]. Replacement of the N-pentyl group, with either an N-5-fluoropentyl or N-5-cyanopentyl group, resulted in substantial increase in CB1 affinity. Chemical substitution of the ketone bridge with a methylene linker led to naphthylmethylindoles (e.g. JWH-175), which have a weaker affinity for the CB1 receptor compared to naphthoylindoles. However, modification of the 1-naphthyl head group, through the introduction of 4-alkoxy- (JWH-081) or 4-halo-substituents (JWH-398) provided access to active cannabimimetics. The most marked increase in potency was observed in 4-alkyl-substituted naphthoylindoles, which led to the JWH- and AM-series (specifically JWH-018 and AM-2201), which dominated the synthetic cannabinoid market for a period [1].

Simplified naphthoylindole derivatives, where the 1-napthyl group was replaced with either a phenylacetyl or benzoyl group were also developed to probe binding to the CB1 receptor. In the case of the phenylacetylindole (JWH-167) the affinity for the CB1-receptor was 10 times less than observed for JWH-018. However, the introduction of 2-alkyl- (JWH-251), 2-alkoxy- (JWH-250) or 2-halo-substituents (JWH-311, JWH203, and JWH-249), led to improved binding [1].

Substitution of the naphthalene group of JWH-018, with a 2-iodophenyl motif results in the benzoylindole derivative AM-679, which exhibits a similar level of binding to CB1 as JHW-018. As with the naphthoylindole family, subsequent replacement of the N-pentyl group, in the AM-679 with an N-5-fluoropentyl tail, resulted in a substantial increase in CB1 affinity (AM-694) [1].

The SCRA 3-acylindole derivatives, such as JWH-018 and AM-2201, emerged in globally in the late 2000s. They are characterized by non-aromatic, bulky alicyclic head groups, such as the adamantylindoles (e.g., AB-001) and tetramethylcyclopropylindoles (e.g., UR-144). As with the naphthoylindole series, the replacement of the N-pentyl group with an N-5-fluoropentyltail resulted in substantial increase in CB1 affinity and led to the emergence of cannabinoids such as 5F-AB-001 and XLR-11 [1].

Similar to the emergence of acylindoles, a variety of acylindazole SCRAs have also emerged. These substances, such as THJ-018, and THJ-2201, feature a modified indazole core but retain specific head and tail groups for optimal CB1 -receptor affinity [1].

In the early to mid-2010s, the NPS market pivoted toward SCRA analogs in which the acyl-linker was substituted by either an ester or an amide linker (e.g., indole-an indazole carboxylates, carboxamides). As with previous classes, affinity for CB1-receptor binding were retained [1].

In 2013, the first two indolecarboxylate SCRAs reported were the quinoline-8-yl derivatives, BB-22 (QUCHIC) and PB-22 (QUIPIC). Cannabimimetic binding of PB-22 was improved by sequential replacement of the quinoline-8-yl- group for a 1-naphthylgroup (CBL-018) and subsequent introduction of terminal fluorine into the N-pentyl tail, leading to a ten-fold increase in CB1 affinity (NM2201). Replacing the N-pentyl tail (in PB-22) with either an N-4-fluorobenzyl group or with an N-5-fluoropentyl chain resulted in FDU-PB-22, FUB-PB-22, and 5F-PB-22 [1].

Indazolecarboxylates are closely related to the indolecarboxylate family of cannabinoids, and some derivatives have been reported to UNODC, including the CBL-018, CBL-2201 analogs, SDB-005, 5F-SDB-005 25, quinoline-8-yl analogs, 5F-NPB-22 51, 52, FUB-NPB-22 53, adamantan-1-yl-1H-indazole-3-carboxylates: APINAC 54–57 and 5F-AKB-57 [1].

As a result of their inherent metabolic instability/toxicity, both the indoleand indazolecarboxylate families have been entirely replaced by the more stable amide (indole- and indazolecarboxamide) classes [1].

In 2012, APICA and its fluorinated derivative, 5F-APICA, became the first indolecarboxamide SCRAs in the NPS market, of which both exhibited moderate CB1 receptor affinity. As a result, a "mix and match" modification of the N-alkyl tails and replacement of the bulky adamantyl head group for either phenyl (N-phenyl-SDB-006), benzyl (SDB-006 and 5F-SDB-006), or 1-naphthyl(NNEI, 5F-NNEI; 5Cl-NNEI, and FDU-NNEI) groups led to a wide variety of products [1].

Phenyl- and benzyl-substituted indolecarboxamides generally exhibit weaker binding to the CB1 receptor compared to their adamantyl- and 1-naphthyl counterparts. The exception to this trend is the sub-family of (2-phenylpropan-2-yl)- (or cumyl-) CB1 agonists, which show significant increases in potency compared to their progenitors SDB-006 and 5F-SDB-006. Several 7-azaindole-3-car boxamide derivatives (also known as the 7AICA-series) have also emerged in the synthetic cannabinoid market, including 5F-AKB-48-7N, CUMYL-5F-P7AICA, CUMYL-4CN-B7AICA, and 5F-PCN [1].

Indazolecarboxamides are a direct extension of the indolecarboxamide family of cannabinoids, where the indole core is replaced with an indazole. Since 2012, various derivatives have been reported, for example SDB-005, 5F-SDB-005 (and analogs); MN-18, and 5F-MN-18. Other examples are the adamantan-1-yl-1H-indazole-3-carboxamides and cumyl-derivatives. These derivatives all show significant increases in cannabimimetic CB1 potency compared to their indole counterparts [1].

Amino Acid Amides

This is an important sub-family within the broader indole- and indazolecarboxamide series of synthetic cannabinoids, which include the valinamides (AB-series), tert-leucinamides (ADB-series), and/or phenylalaninamide (APP-series). The incorporation of esters like, methyl valinate (AMB- or MMB-series), ethyl valinate (AEB- or EMB-series), methyl tert-leucinate (MDMB-series), and/or ethyl tert-leucinate (EDMB-series) is also possible [1].

Unlike the previously discussed cannabimimetics, which are achiral, these SCRAs contain an asymmetric carbon. In theory, these compounds are present in two enantiomeric forms, dependent on the source and enantio-purity of the precursor chemicals used. In most cases, a higher potency at the CB1 receptor is observed for the (S)-enantiomer over the (R)-enantiomers. In seized samples, the more active enantiomer appears to predominate [1].

As with previous generations, the indole-valinamide synthetic cannabinoids with N-alkylated tail groups bearing 4 or 5 carbons exhibit nanomolar CB1 affinity (e.g., AB-PICA). Modification of the N-pentyl group, with either an N-5-fluoropentyl- (5F-AB-PICA) or aromatic N-4-fluorobenzyl- (AB-FUBICA), tail resulted in substantial increase in CB1 affinity. Compounds containing other side chains such as N-4-cyanobutyl (4CN-AB-BUTICA), N-cyclohexylmethyl (AB-CHMICA), and N-penten-4yl (AB-4en-PICA) have also been reported. Replacement of the indole core with an indazole (e.g., AB-PICA versus AB-PINACA) leads to a ten-fold increase in potency in each congeneric derivative. A similar increase in CB1-binding affinity was seen within the analogous indoleand indazole-tert-leucinamide [ADB-series] derivatives. The same was not observed in the APP-series derived from phenylalanidamide, where the presence of the bulky aromatic group significantly reduces CB1 cannabimimetic activity in many cases. Further chemical modification of the tail groups or replacement of the core with a 7-azaindole scaffold in the most active ADB-series resulted in an increase in the variety of potent and potentially more harmful analogs on the market [1].

An extension of this sub-family has also emerged, where the amino acid amide group was replaced with either a commercially available chiral methyl valinate (AMB- or MMB-series), ethyl valinate (AEB- or EMB-series), methyl tert-leucinate (MDMB-series), or ethyl tert-leucinate (EDMB-series) group. Similar to the AB-, ADB-, and APP-series, in most cases, a higher potency at the CB1 receptor is observed for the (S)-enantiomer over the (R)-enantiomers. The AMB-/MMB- and MDMB-series of derivatives bearing N-4-fluoropentyl, N-5-fluoropentyl and N-penten-4-ylgroups show the same trends, except for in terms of binding affinity as their amide counterparts with indazoles observed to be more potent than indoles and the tert-leucinate derivatives more potent than the valinate derivatives [1].

The N-4-fluorobenzyl-, N-cyclohexylmethyl-, N-4-cyanobutyl-, N-5-chloropentyl-, and 7-azaindole derivatives show similar trends in terms of their CB1 -binding affinities as their corresponding amide counterparts. A small number of ethyl valinate (EMB-) and tert-leucinate (EDMB-) derivatives have also been reported [1].

After the national control of some indoles, indazole, and benzimidazole-derived synthetic cannabinoids, the NPS market again shifted towards previously unexplored chemical structures. In 2014, tricyclic synthetic cannabinoids, such as the carbazole and γ-carboline were first identified and exhibited moderate CB1 affinity. Between 2017 and 2020 several γ-carboline analogs have emerged in which the N-pentyl tail has been replaced with either a N-5-halopentyl or cycloalkyl group [1].

In 2021, new substances with previously unencountered and/or not well-characterized structural modifications appeared on the market, including the weak CB1 binding N-alkylisatin-acylhydrazone, MDA-19 (also known as BZO-HEXOXIZID), and its related analogs [1]

The 2C-series sub-group is the largest of the three hallucinogenic phenethylamines. The powerful hallucinogen 2C-B was the first 2C synthesized, in 1974, by simple alterations to the natural phenylethylamine molecule mescaline. The more commonly encountered 2Cs in the United States are 2C-B and 2C-T-7, known by the street names Nexus, Bromo, Blue Mystic, and T7 [1,15].

The effect following oral use in the lower dose range (<8 mg for 2C-B and 10–50 mg for 2C-T-7) lasts six to eight hours and is often described as relaxation, awareness of integration between sensory perception and emotional state, and euphoria with increased body awareness and enhanced receptiveness of visual, auditory, olfactory, and tactile sensation. Dosing in the upper limits results in greater stimulant effects and a state of substantially greater intoxication. Even higher dosing produces LSD-like visual and auditory effects and potentially extremely fearful hallucinations and morbid delusions. User reports of 2C drug effects describe a blend of MDMA-like empathy and entactogenic effects with LSD-like psychedelic effects. 2C-B is used primarily as a club drug in the rave culture and circuit party scene, where some users ingest 2C-B in combination with LSD (a "banana split") or MDMA (a "party pack"). Several fatalities have been reported from co-ingestion of 2C-T-7 and MDMA [51,53].

Possible adverse effects include nausea, vomiting, agitation, tachycardia, hypertension, respiratory depression, seizures, psychosis, and suicidal thoughts. Excited delirium with agitation and violent behavior, hyperactivity, hyperthermia, and cardiopulmonary arrest have been documented following 2C use. Immediate action is required with excited delirium, hyperthermia, and seizure activity, because presence of vomiting, agitated behavior, and seizures are risk factors for fatal 2C toxicity [1,18].

The introduction of a methyl-group in the alpha position of 2C-series substances provides access to ring-substituted amphetamine derivatives, known as the D-series. Included are 4-iodo-2,5-dimethoxyamphetamine (DOI) and the trimethoxyamphetamines (TMA-2 and TMA-6). Compared with the 2C-series, D-series substances are metabolically stable to monoamine oxidases in the body, making them significantly more potent with a duration of action up to three times greater (6 to 10 hours versus 16 to 30). Reported adverse effects associated with the use of D-series derivatives include agitation, tachycardia, mydriasis, hallucinations, severe limb ischemia, seizures, liver and renal failure [1,8].

The N-benzylphenethylamines (NBOMe) series was first developed in the early to mid-2000s for the purpose of researching mammalian serotonin receptor distribution. Initial Internet discussion and law enforcement attention both occurred in 2010. They are commonly known by the street names N-Bomb, Smiles, 25I, 25C, and 25B [32].

As noted, the NBOMes are synthesized from 2C phenethylamines by the addition of a 2-methoxybenzyl (MeOB) unit onto the nitrogen molecule. This molecular appendage confers greater potency than its 2C counterpart; for example, the dose of 2C-I is roughly 20 mg versus 50–100 mcg with 25I-NBOMe. The hallucinogenic effects are mediated by highly potent and selective agonist activity at 5-HT2A receptors [1,32].

The NBOMe series is sold as powder, liquid solution, or soaked into blotter paper. NBOMe appears in products sold as LSD, a widespread counterfeiting practice that is encouraged by the cheaper cost of NBOMe. This poses a potentially serious health risk to the user, who instead of ingesting the physiologically benign LSD, unsuspectingly ingests NBOMe and risks potentially severe and fatal adverse effects [33].

The effects of NBOMe last 6 to 10 hours with sublingual ingestion. Users report desired effects of euphoria, mental/physical stimulation, feelings of love/empathy, altered consciousness, and unusual body sensations. Negative effects include confusion, shaking, nausea, insomnia, paranoia, and intense negative emotions. Users with severe NBOMe toxicity show violent, severely agitated, and hallucinating presentations and require hospitalization, as hyperthermia, tachycardia, hypertension, seizures, metabolic acidosis, elevated creatine kinase, and acute renal injury are usually present. Even small amounts can cause seizures, cardiac and respiratory arrest, and death. Many fatalities have occurred following NBOMe use, typically preceded by excited delirium [1,32].

Benzofurans include 1-(benzofuran-5-yl)-propan-2-amine (5-APB), 6-APB, and their dihydro-derivatives 5-APDB and 6-APDB. Benzofurans are analogs of MDMA and MDA, first synthesized in the 1990s at Purdue University for researching structure-activity relationships of MDMA-like molecules. In 2010, 5/6-APB entered the UK market as an MDMA replacement "legal high" under the brand name Benzofury (derived from benzofuran) and became very popular. Other benzofurans include IAP and 5-APDI, which replace both oxygen atoms of MDA with methylene groups; 5- and 6-API, which replace the oxygen atom in the heterocyclic rings of 5/6-APB with a nitrogen atom; and 5-MAPB, an N-methyl analog of 5-APB [1,8,15].

Benzofurans are dopamine, norepinephrine, and serotonin inhibitors, with greatest potency at dopamine and norepinephrine receptors. As full 5-HT2B agonists, 5/6-APB may be cardiotoxic with long-term use. User reports describe an empathogenic and stimulant effect, with 5-APB more potent than 6-APB. Several fatalities have been attributed to benzofurans, with hyperpyrexia noted in several cases. Emergency department admissions for benzofuran toxicity have noted tachycardia, elevated blood pressure, and fever [1,8].

Benzodifurans are termed the "fly" drugs in reference to their insect-resembling molecular structure. They include tetrahydrobenzodifuranyl (Fly), 2C-B-Fly, 3C-B-Fly, and the most potent and widely used drug of this category, benzodifuranyl aminoalkane (Bromo-Dragonfly or B-Fly). The phenyl ring bound between two dihydrofuran rings in B-Fly produces much greater potency and duration of action than most phenethylamine derivatives. B-Fly mechanism of action is mediated primarily by agonist activity at 5-HT2A receptors and, to some degree, 5-HT1 and 5-HT2C receptors [1,8,15].

Recreational use of B-Fly was first noted in 2001 and became widespread in 2008, primarily through Internet mediation [63]. B-Fly is sold for oral use in blotter paper or liquid. Following a typical 200–800 mcg dose, the onset of effects can take six hours. Many users assume the initial dose ineffective and ingest another dose or other substances. The drug effect commonly lasts two to three days and is described as profound hallucinations (mainly visual, with geometric patterns and lights), sound alterations, a sense of connection/belonging with other realities, a sense of peace and well-being, emotional stimulation, and meeting with metaphysical entities. Commonly reported adverse effects include nausea and vomiting, headache, tachycardia, elevated blood pressure, lung collapse, gastrointestinal disturbances, muscle tension, tremor, anxiety, panic attacks, arrhythmias, heart murmurs, convulsions, flashbacks, memory disturbances, confusion, and paranoid ideation. Several fatalities have been reported in Europe, but attribution is unclear, as polysubstance use (particularly with ketamine) is common with B-Fly [1,8,15].

Introduction of methyl- or ethyl-branching into the ethylamino sidechain, provides access to alpha-methyltryptamine (AMT), 5-MeOAMT, and alpha-ethyltryptamine (AET). AMT and AET were developed as antidepressants in the 1960s by Upjohn but were withdrawn from brief clinical use due to the risk for psychoses and other adverse effects. With a 15–40 mg oral dose of AMT, effects have onset in three to four hours. Visual hallucinations, altered sensory perception, and euphoria persist for 12 to 24 hours. Frequently reported adverse effects include anxiety, nausea, moderately severe dysphoria, and next-day depression. AET produces psychedelic, stimulant, and entactogenic effects but may induce serotonin neurotoxicity [1,8,39].

Other indole ring-unsubstituted tryptamines include DMT, DET, dipropyltryptamine (DPT), and DiPT. DPT was synthesized in the 1950s and was first used in 1973 as an adjunct to psychotherapy in the treatment of alcoholism. An oral dose of 100–250 mg induces psychedelic effects, with increased music and color intensity, flashes of light and sparkles, ego loss, and seeing apparitions of faces. These effects last two to four hours [1,8,39].

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), is a 4-position ring-substituted tryptamine, producing hallucinogen effects similar to those of LSD and mescaline, and is the major active constituent several species of hallucinogenic mushrooms ("magic mushrooms"). Psilocybin is rapidly dephosphorylated to psilocin (4-hydroxy-N,N-dimethyltryptamine, 4-HO-DMT) by alkaline phosphatase. Although psilocin and psilocybin have been available on the illicit market since the 1960s, the recreational use of other 4-substituted tryptamines is a more recent development, fueled by marketing and distribution via the Internet. It has been documented that most 4-substituted tryptamines produce psilocybin-like psychedelic effects [1,39].

All 5-position ring-substituted tryptamines inhibit monoamine reuptake but have few monoamine releasing effects. 5-MeO-AMT is a psychedelic tryptamine with structural similarity to amphetamines. Oral use of 2.5–4.5 mg produces effects lasting 12 to 18 hours. Excessive dosing can induce sympathomimetic effects and has led to several hospitalizations and fatalities [40].

5-MeO-DiPT, termed Foxy or Foxy Methoxy, was first synthesized by Andrew Shulgin and emerged as a drug of abuse in 1999. The effects resemble 2C-B, with a psychoactive threshold of 4 mg. Doses of 6–20 mg produce full-blown effects that peak at 60 to 90 minutes and last three to six hours. The initial nausea and muscular hyperreflexia are followed by euphoria, relaxation with emotional enhancement, talkativeness, and behavioral disinhibition. Higher doses can produce abstract closed-eye imagery [40]. Adverse effects include restlessness, agitation, gastrointestinal distress, muscle tension, and rhabdomyolysis. Fatalities have been associated with 5-MeO-DiPT [1].

5-MeO-MiPT or "Moxy" is an analog of 5-MeO-DiPT. Following an oral dose of 4–6 mg, this drug produces euphoria, increased tactile sensations, relaxation, and visual distortions that dissipate by 10 hours, followed by difficulty sleeping [40].

Excited delirium syndrome, also referred to more recently as agitated delirium, is the most serious NPS-induced toxicity, is a severe, life-threatening state of agitated delirium and autonomic dysregulation. This syndrome is characterized by sympathetic hyperarousal (e.g., hyperthermia, vital sign abnormalities, metabolic acidosis), delirium (altered consciousness with diminished awareness of one's environment), rhabdomyolysis, and agitated or violent behavior. Patients with excited delirium are incoherent and combative; emergency department arrival is often by EMS transport or police escort in physical restraints. Many sustain traumatic injuries before first responder contact and intensely struggle even when struggle is futile, resulting in self-harm. Some patients may strip naked, reflecting the combined hyperthermia and altered mental status [28,58].

Stimulant toxicity resulting in excited delirium syndrome has been described with MDMA, cocaine, amphetamine, and more recently, NPS such as cathinones and cannabimimetics. The hyper-dopaminergic state associated with intoxication with these drugs overloads dopamine circuitry with electrochemical signaling, triggering a surge in extreme motor hyperactivity, delirium, agitation, and violent behavior. Action pathways lead to peripheral sympathomimetic stimulation that predisposes to cardiac arrhythmia and cardiomyopathy, and with sufficient activation of the neurocardiac axis, sudden death. Autopsy results have shown a diminished concentration of D3 dopamine receptors relative to controls, suggesting a deficit in normal compensatory measures in response to rapid changes in dopamine levels [28,58].

Hyperthermia contributes to excited delirium-associated morbidity and mortality and primarily results from agitation that drives muscular hyperactivity, rhabdomyolysis, and renal failure. Even with patient survival of an initial cardiac arrest, persistent hyperthermia contributes to the developing coagulopathy, rhabdomyolysis, and multisystem organ failure [41,58].

Effective Calming of Patients with Excited Delirium Syndrome

The ability of EMS or emergency department staff to safely subdue patients with excited delirium has been elusive. Delays in medical treatment and the use of conventional restraints can be fatal. The behavioral symptoms of excited delirium impose a serious safety hazard to EMS, emergency department staff, and the patient. TASER and physical restraints are standard control measures but produce further destruction of muscle tissue, exacerbating the risks of subsequent renal failure and cardiopulmonary collapse. Benzodiazepines and haloperidol are used by some EMS to calm patients with excited delirium before attempting emergency transport. In this setting, IV administration is usually impossible, intramuscular administration delays the onset, and the dose required to sedate violent patients risks adverse hemodynamic and respiratory complications. Antipsychotic drugs interfere with already-compromised dopamine function [30].

Intramuscular ketamine has rapid onset and efficacy, a wide therapeutic window, and favorable side effect profile. It is becoming favored by EMS for calming patients with excited delirium before emergency transport with support from several studies. However, some patients develop laryngospasm and hypoxia, resolved by endotracheal intubation. In one study of 52 patients receiving ketamine 4 mg/kg IM, effective sedation and medical control was achieved within 150 seconds in 96% of cases; all remained sedated following emergency department arrival (mean: 19 minutes) [31]. In another study of 35 agitated, combative patients with possible excited delirium, 91% were successfully sedated by ketamine IM (mean dose: 324 mg), 17% required additional post-ketamine sedation by EMS or emergency department staff, and 23% required post-ketamine intubation. Emergence reactions, well described with ketamine, also developed but were resolved with benzodiazepines. Rapid calming from ketamine reduces extreme physiologic stress from extended struggles with police and continued agitation with physical restraints. Excited delirium syndrome requires IV initiation to begin end-organ, life-preserving treatment, which is nearly impossible until severely agitated, combative patients are sedated [30,31].

Sympathomimetic toxidrome resembles excited delirium, differing by dominant hyperadrenergic symptoms of tachycardia, hypertension, nausea/vomiting, and diaphoresis and a lack of violent agitation. Excited delirium syndrome and sympathomimetic toxidrome can co-occur. The presumed underlying hyperdopaminergic and hyperadrenergic states of excited delirium and sympathomimetic toxidrome, respectively, are intertwined. As such, co-occurrence in NPS toxicity is probably frequent, and management is highly similar [15,18].

Serotonin syndrome is a state of excess serotonin activity from serotonergic agent overdose or synergistic toxicity. Serotonin syndrome shares some features with excited delirium and sympathomimetic toxidrome, but patients are rarely aggressive and violent. Patients typically present with psychomotor agitation, and cognitive (e.g., confusion, delirium), neuromuscular (e.g., akathisia, ataxia, myoclonus, hyper-reflexia), and autonomic (e.g., dizziness, nausea/vomiting, tachycardia, sweating) symptoms. It can be differentiated from sympathomimetic toxidrome by the presence of shivering, rigidity, myoclonus, and hyper-reflexia. Serotonin syndrome is characterized by a rapid onset of neuromuscular symptoms with markedly increased muscle tone, along with shivering, tremors, hyper-reflexia, akathisia, ataxia, and myoclonus. Sweating may decrease and contraction of opposing muscle groups generates heat more rapidly than vasodilatation, leading to hyperpyrexia and cardiovascular instability. The mortality rate is 10% to 15% [8,15].

Acute Hyponatremia

Acute hyponatremia has led to numerous MDMA fatalities. These deaths usually result from prolonged (8 to 12 hours) dancing to electronic dance music (e.g., techno, house). Indoor settings with poor ventilation and high ambient temperature contribute further. Hyperthermic complications from MDMA stem from exertional hyperpyrexia, hyponatremia, and serotonin syndrome [27,42].

Anticholinergic toxidromes can resemble NPS toxicity, with altered consciousness, agitation, confusion, disorientation, delirium, hallucinations, tachycardia, tachypnea, and hyperthermia. Sympathomimetic toxidrome may be differentiated from anticholinergic toxidromes by presence of marked diaphoresis (instead of dry skin) and lack of bowel sounds [8,18]. The presence of neuromuscular abnormalities is specific to serotonin syndrome and is not seen in patients with anticholinergic toxidromes.

A GABA agonist withdrawal syndrome from substances such as alcohol or benzodiazepines is a common medical condition that shares autonomic hyperarousal, agitation, and altered mental status with NPS toxicity. Neurologic trauma or disease, including traumatic brain injury, hydrocephalus, brain tumor, and subarachnoid or intracerebral hemorrhage, can produce an intense autonomic dysregulation syndrome similar to that seen with NPS use. These patients may also display hypertension, fever, tachycardia, tachypnea, and pupillary dilation [1,28,30].

Some psychiatric disorders may have similar presentations to acute NPS toxicity, including bipolar disorder and paranoid schizophrenia. Patients may display an emotional rage reaction in response to acute psychologic stressors. In addition, psychotropic drug withdrawal and emergent symptoms from medication noncompliance may precipitate symptoms similar to an excited delirium or serotonin syndrome.

Systemic inflammatory response syndrome (SIRS) is related to systemic inflammation, organ dysfunction, or organ failure, and is broadly classified as infectious or noninfectious. With infection, the condition is termed sepsis. Noninfectious SIRS origins include trauma, burns, pancreatitis, ischemia, and hemorrhage, and dysregulated and uninhibited pro-inflammatory pathways result in altered mental status, fever, or hyperdynamic vital signs [28].

Encephalitis of viral, bacterial, fungal, or autoimmune origin can manifest in neuropsychiatric disturbances and altered mental status with severe headache, fever, confusion, agitation, personality changes, seizures, hallucinations, or impairment in speech or hearing. Limbic encephalitis of paraneoplastic origin can produce severe neuropsychiatric symptoms, marked agitation, and autonomic dysfunction [28].

Malignant catatonia is a neuropsychiatric syndrome seldom seen clinically, is highly lethal, and initially presents as nonspecific insomnia and mood changes, progressing to severe anxiety, delusions, hallucinations, and agitation. Other symptoms can include severe, nonpurposeful hyperkinetic movements, high fever, tachycardia, and labile blood pressure [28].

Endocrine system disorders can appear as agitation, autonomic instability, and fever. In thyrotoxic crisis, cardiac failure, arrhythmia, or hyperthermia can result from a massive surge in thyroid hormone. Tumors of the sympathetic ganglia can produce hypertension, tachycardia, sweating, and panic attacks from increased sympathetic tone. Less commonly, fever and delirious agitation may be noted [28]. In patients with diabetes, hypoglycemia may precipitate violent outbursts and an appearance of intoxication. Hypoglycemia may be diagnosed rapidly and conclusively via blood glucose testing and glucose response.

If treatment of excited delirium or sympathomimetic toxidrome is neglected, delayed, or inadequate, the outcome is often multiple end-organ damage or death. The most essential aspect of the management of cathinone toxicity is rapid, aggressive sedation with benzodiazepines. Benzodiazepines are the agents of choice because they decrease excessive heart rate, blood pressure, neural stimulation, and muscular activity; prevent seizures; protect against physical violence; and reduce muscular hyperactivity that drives fever, rhabdomyolysis, and renal failure. Benzodiazepines have a wide safety margin and, contrary to common belief, do not dangerously decrease cardiovascular or respiratory parameters unless used with potent sedatives. Immediate calming may require IM lorazepam, midazolam, or ketamine to allow for safe placement of IV access. With access in place, IV diazepam may be initiated, the preferred agent for effective rapid titration because full onset of each dose occurs within five minutes, allowing repeat dosing without the "overshooting" risk with slower-onset lorazepam. Patients may require very high doses for effective sedation. Propofol or barbiturates in those appearing refractory to high-dose benzodiazepine [18,28,30]. Antipsychotic drugs interfere with already-compromised systemic dopaminergic function and should be avoided in patients with suspected excited delirium.

Management of serotonin syndrome targets agitation, hyperthermia, and autonomic dysfunction. Benzodiazepines are preferred to induce sedation and reduce muscle rigidity. With causal substance(s) typically unidentified and benzodiazepine efficacy across NPS toxicity syndromes, benzodiazepines should be used instead of serotonin antagonists [30].

All toxicities with hyperpyrexia require aggressive cooling through high-rate IV fluids and external cooling measures. The combination of sedation, fluids, and cooling reverses hyperthermia and metabolic acidosis and prevents further muscular and hepatorenal injury. Enteral or parenteral vasodilators should be used for persistent hypertension, while beta-blockers should be avoided because unopposed alpha-receptor stimulation can induce systemic vasoconstriction. Sodium bicarbonate may be considered for rhabdomyolysis and acidosis. Antipyretics are ineffective for hyperthermia because the origin is increased muscular activity, not hypothalamic temperature dysregulation [30].

Following resolution of the autonomic storm and return to normal reflexes and muscle tone, clinicians should be aware that psychosis, dysphoria, and irritable unrest can persist in patients hospitalized for NPS toxicity after medical stability is achieved. These lingering psychiatric symptoms best respond to dopamine blockade with neuroleptics. This aspect of persistent cathinone toxicity makes post-hospital care challenging and heightens the importance of care providers in multiple specialties to understand this toxidrome and the associated phases of illness [30,41]. Fatalities following cannabimimetic use have occurred in patients discharged home with lingering paranoia and depression.

Helping motivate and empower patients with NPS use disorder to seek help is a challenge. Research suggests many patients with NPS use disorder do not identify as needing conventional drug treatment or do not want to seek help due to the illicit nature of NPS. Hospitalization for NPS overdose/toxicity presents an excellent window of opportunity (the "teachable moment") for advising patients to decrease their substance use or to engage them in treatment. Provider awareness and patient education are cornerstones of public health initiatives to confront the new challenges from NPS. Simple admonitions are insufficient, and adolescents/younger adults are wary of any communication with a judgmental, heavy-handed abstinence tone [50]. Patients identified with any substance use disorder in the emergency department or inpatient setting should be linked to information on local and national addiction treatment resources (Table 9).

Because patients with problematic NPS use may be ambivalent about changing behavior, clinicians should demonstrate respect for patient autonomy by expressing empathy without confrontation. Providing appropriate, accurate information on the relative risks and unknown harms of NPS empowers patients in making informed decisions to continue NPS use, attempt to quit, or seek treatment [50].

In the primary care setting, patients with NPS-related problems may present with concerns over their NPS use or with problems they suspect are NPS-related. Alternatively, patients may describe an NPS-related problem without linking it to NPS use. Motivational interviewing is suggested because this technique is proven useful in resolving patient ambivalence over change with numerous clinical conditions. This approach involves first appreciating and addressing patient concerns and withholding advice until greater clarity emerges. This empowers active patient participation and facilitates positive behavioral change. To begin this process, gain patient permission before questioning about substance use. If granted, mention confidentiality. If concern is from a family member, explore further, ask about their coping, and provide info on relevant support if needed [50]. With assessment of patients acknowledging drug use-related problems, invite active patient contribution by asking open-ended questions, such as:

To help build rapport, ask about drug jargon and drug effects. Giving feedback with specific reference to patient concerns can help patients re-frame their drug use and consequences.

After the basic situation and clinical picture has been established, the next steps should be determined. Further questions may include:

This can involve further information about the presenting problem or drug use, harm-reduction advice, guidance on managing physical or psychiatric problems, exploration of abstinence, or specialist referral.

Patients who clearly link drug use with a problem are likely to ask questions and be receptive to expert input. Apply a circular process to engage patient interest:

Avoid assuming the patient wants to change or needs expert help to change. Instead, introduce the concept of change by asking:

If a patient expresses the wish to change, ask how he or she might do this and whether professional support is needed. In patients unsure about what they should do, consider harm-reduction advice. As little is known about NPS, give general harm reduction advice such as limiting use, a period of cessation to observe improvement in health concerns, and total avoidance in high-risk patients (e.g., those with a history of psychiatric illness, addiction). The appointment should end with permission to revisit the subject in the future [50].

Patients in treatment for NPS use disorder may need to address premorbid or NPS-induced psychiatric or medical conditions or symptoms. As with other patients, those recovering from NPS use disorder probably require long-term support, professional contact, and possibly multiple short-term acute treatment episodes. Treatment typically involves components similar to those in general use, including individual and group counseling, cognitive-behavioral therapy, motivational enhancement therapy, and 12-step facilitation. Family members should be considered for involvement in the treatment program, especially with adolescent or young adult patients. Little data are available to guide pharmacologic management of acute and post-acute NPS withdrawal symptoms and ongoing NPS craving. Treatment is more complex for patients with backgrounds of polysubstance abuse, young age at initiation of regular drug use, lingering neuropsychologic impairment, or psychiatric disorders. Patients with intermittent NPS use in social settings may perceive they have less of a problem [30,50]. Encouragement of 12-step program involvement, such as Narcotics Anonymous, can provide patients with the means for support, a non-substance-using social network, and other benefits conducive to recovery.