NPS represents a broadly diverse category of novel substances, primarily those synthesized from phenethylamines, amphetamines, cathinones, aminoindanes, benzofurans, tryptamines, opioids, and arylcyclohexylamines; however, cannabimimetics and natural botanical products are also included. The molecular structure of common drugs is altered to produce a novel drug agent with shared pharmacologic and clinical properties of the parent drug that, owing to the novel molecular structure, falls outside of legal and regulatory control. This allows for their distribution and sales as "legal" alternatives to the established but banned drugs [6,7,8].

NPS are marketed as purportedly non-ingestible consumer products, most commonly legal highs, herbal incense (cannabimimetics), bath salts (synthetic cathinones), and also as potpourri, plant food, room deodorizer, and electronic-device cleaner [9,10]. All NPS are labeled by distributors "not for human consumption" in order to evade controlled substance analogue statutes for which prosecution requires the intent for human consumption. NPS purchased on the Internet are often labeled "research chemicals" (or RC), "intended for scientific research only," and "not for human consumption" [8,10]. Cannabimimetics now appear in liquid form for use in electronic cigarettes and vaporizer devices [12].

Although NPS emerged domestically in 2008, use has been widespread in Europe for years, prompted by recreational drug scarcity. Banned in 1985, MDMA (also referred to as Ecstasy) has remained very popular for its mild stimulant, euphoric, and entactogenic/empathogenic effects. The standard MDMA chemical precursor, safrole, is extracted from camphor trees (Cinnamomum camphora) in Southeast Asia. During the 1990s and 2000s, interdiction of safrole shipments into Europe and safrole oil at extraction sites limited precursor supplies for MDMA production, decreasing MDMA purity and availability in Europe. Another precursor, piperonyl methyl ketone (PMK), is banned, but in 2012, Chinese chemists introduced PMK-glycidate, a precursor easily converted to PMK. This reversed long-term scarcity, and from 2013 to 2015, Europe was flooded with high-potency MDMA pills produced by labs in the Netherlands and Belgium, with reports in 2016 indicating that seizures and stopped shipments were being seen in France, Bulgaria, and Spain, suggesting diversifying trafficking routes [14,15]. The MDMA resurgence continues, with the 2018 European Drug Report indicating 1 kg of piperonal, 1,077 liters of PMK, 63 liters of safrole, 5,905 kg PMK-glycidate, and 123 kg of N-tert-butoxycarbonyl-MDMA (Nt-BOC-MDMA) seized in 2016. Additionally, stopped shipment of 7,700 kg of piperonal and 1,000 kg of PMK-glycidate occurred in Europe in 2016 [14]. The European Drug Report indicates increased rates of seizure for both PMK and non-scheduled chemicals (PMK-glycidate and Nt-BOC-MDMA) for MDMA production [14].

The number of recently emergent NPS is unprecedented. In the United States between 2009 and 2014, 233 new synthetic compounds were identified, including 95 cannabimimetics, 51 synthetic cathinones, and 87 other NPS compounds [12]. The United Nations reported that 803 NPS were identified by member nations between 2009 and 2017, including cannabimimetics (31%), synthetic cathinones (18%), and phenethylamines (17%) [47]. As of late 2020, the European Union was tracking approximately 830 psychoactive substances, 46 of which were first reported in 2020, and almost all of which are NPS [11,14]. These figures are constantly becoming outdated and staying abreast of rapid changes in the NPS market is difficult [11,13].

A study of cannabimimetic users found the majority used these substances 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 cannabimimetics from someone using the substances to avoid drug-testing detection [40].

The difficulty in detecting cannabimimetics and cathinones by urine drug screens has made their use attractive to active U.S. Armed Forces members. Beginning in early 2011, the extent these drugs were used became evident, with reports of numerous incidents involving the detection and subsequent discharge of large numbers of service members from individual military bases or deployments. Among these reports was an event in 2011 in which an Army combat medic with two deployments to Iraq asphyxiated his young son and then shot and killed his wife and himself during synthetic cathinone intoxication [1]. Increasingly, soldiers have begun requiring emergency department admission or police intervention for medical and behavioral toxicity from these agents. These cases raised sufficient alarm for the military to enact regulations banning the use, possession, or sales of cannabimimetics and cathinones in 2011 [41].

Hard data are difficult to find, but persons on parole and/or probation have been mentioned as among the most likely groups to use NPS for escaping detection by urine drug testing. Considering the number on probation/parole with untreated addiction and limited resources and the availability of a low-cost street purchase sufficient for intoxication, this may represent a sizeable number of NPS users [19,31].

Music and club subcultures 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 [25]. Efforts to improve safety through harm-reduction approaches (e.g., testing pills, information dissemination) developed during this period.

Polysubstance ingestion before, during, and after NPS use is common and can occur without intent by the frequent addition of multiple NPS and other psychoactives to NPS products. NPS users often co-ingest cocaine, amphetamines, MDMA, caffeine, hallucinogens, Mitragyna speciosa (kratom), and/or cathinones to enhance stimulant and entactogen effects; alcohol and beta-blockers to suppress tachycardia; zopiclone to produce visual hallucinations; pregabalin, omeprazole, and domperidone to counteract stomach pain; and cannabis and benzodiazepines to counteract anxiety [43]. Self-administration of the second-generation antipsychotic drug olanzapine has become widely endorsed on Internet forums as the "ideal" molecule to terminate NPS-related psychotic crises/"bad trips," typically at a dosage range of 5–50 mg/day [44].

Phenethylamine, or phenylethylamine, is the parent molecule of many psychoactive substances, including synthetic cathinones, benzofurans and benzodifurans, the 2C and NBOMe series, aminoindanes, mescaline, and the classic recreational drugs amphetamine, methamphetamine, and MDMA (Figure 1). The structural similarity of phenethylamine to the neurotransmitter dopamine is readily apparent.

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 [72]. 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 [48,71,73].

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 [23]. Several fatalities have resulted from co-ingesting 2C-T-7 and MDMA. Treatment of 2C toxicity is supportive, but 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 [18,55].

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 [63].

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 [48].

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 [73]. 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 [1]. 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 [88].

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 [9,16,73].

Entering the domestic NPS market in late 2010, MDPV quickly rose in prominence and notoriety [77]. 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 [48,74].

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") [48,80]. 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 [73].

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 [6,80,92]. 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 [42]. Cathinones closely resemble amphetamines in molecular structure, but differ by greater potential for severe and protracted adverse effects, potentially even from a single dose [92].

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 [50,73]. 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 [93,94,95,96].

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 [74,98]. 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 [74]. 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 [94].

The psychoactive components of cannabimimetics are primarily manufactured in China. These bulk chemicals are shipped as powder or dissolved in acetone or other solvents to U.S. distributors, who spray or coat the compound onto dried herbs and package the product for retail sales as herbal incense or potpourri. Of the numerous brands cannabimimetics have sold under, "Spice" has the highest name recognition and has become synonymous with cannabimimetic products. Herbal products saturated with cannabimimetics were introduced in Europe in 2004 and the United States in 2008, marketed as legal-high alternatives to cannabis [6,7,101]. Spice products were smoked until the entrance of oral/e-liquid/injectable cannabimimetic formulations for use in e-cigarettes or "vaping." Identically labeled products vary by cannabimimetic dosage, composition, and concentration. Some contain multiple cannabimimetic agents and other substances identified in samples as psychoactive herbs and plants, benzodiazepines, tryptamines, phenethylamines, NBOMe compounds, cathinones, and opioids [26,102].

THC and cannabimimetics bind and activate CB1 receptors to produce their euphoric effects. Compared to the partial CB1 agonist THC, full agonist cannabimimetics have greater potency, with toxicity and overdose potential uncharacteristic of cannabis [106]. As a partial agonist, THC is limited in the extent it activates CB1 and shows a direct dose-response effect until a plateau is reached, with further dose escalation failing to increase drug effect. This partial agonist property contributes to the infrequent toxicity from cannabis use and the perception of cannabis as a "safe" drug. In contrast, the full CB1 agonist cannabimimetics do not possess a dose-response plateau and further use increases overdose and toxicity risk [103].

Cannabimimetics produce a substantially greater drug effect than THC, with CB1 receptor binding affinities 5 to 10,000 times greater and significantly higher dose-response efficacy. CB1 agonists inhibit GABAergic neurons that project to the nucleus accumbens, which disinhibits nucleus accumbens dopaminergic neurons that activate the mesolimbic dopaminergic pathways and contribute to the rewarding properties and abuse potential of cannabinoids. Because cannabimimetics more powerfully activate CB1, they produce more intense euphoria and reward. This greater inhibition of GABA-mediated neurotransmission also disrupts the balance of GABA/glutamate release in neuronal projections from the prefrontal cortex, which over-activates dopaminergic systems in the prefrontal cortex and striatum, inducing paranoia, agitation, anxiety, psychoses, and convulsions [18,102].

The quality and intensity of adverse effects also differ. Unlike cannabis, cannabimimetics can induce severe agitation, psychosis, and paranoid delusions; command hallucinations are more likely with prolonged, heavy use. The greatest safety concern is psychosis, which can occur in persons without previous history and persist five months or longer [109]. Young and first-time users may be particularly vulnerable to cannabimimetic-induced psychoses [110]. The severity of distress during panic attacks and other psychologic effects has driven some cannabimimetic users to suicide [50].

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 hyper-reflexia are followed by euphoria, relaxation with emotional enhancement, talkativeness, and behavioral disinhibition. Higher doses can produce abstract closed-eye imagery [113]. Adverse effects include restlessness, agitation, gastrointestinal distress, muscle tension, and rhabdomyolysis. Fatalities have been associated with 5-MeO-DiPT [47].

Salvia divinorum is a member of the mint family native to Oaxaca, Mexico, and has been used by Mazatec shamans for divination and spiritual healing for more than 500 years [121]. It is used in the United States for its intense hallucinogenic effects, sometimes under the street names Sally-D, Diviner's Sage, Magic Mint, and Mystic Sage [122]. Salvinorin A, the primary psychoactive constituent, is a potent and selective kappa opioid receptor agonist that, unlike LSD, psilocybin, and DMT, lacks serotonin receptor activity [122]. Salvinorin A is the most highly potent known hallucinogen found in nature.

As discussed, excited delirium syndrome, 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 [125,126].

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 [19]. 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 [127]. 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 [132].

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 [132,133]. 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) [132]. 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 [133]. Emergence reactions, well described with ketamine, also developed but were resolved with benzodiazepines [134,135]. 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 [132,133,134].

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 [93,137,138]. 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 [139,140,141].

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.

If treatment of excited delirium or sympathomimetic toxidrome is neglected, delayed, or inadequate, the outcome is often multiple end-organ damage or death [94]. 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 [18,93,94,146,147,148]. Antipsychotic drugs interfere with already-compromised systemic dopaminergic function and should be avoided in patients with suspected excited delirium [127].

A survey found that 36% of cannabimimetic users experienced tolerance and 12% developed dependence [102]. Long-term cannabimimetic use has been associated with a severe withdrawal syndrome with drug craving, tachycardia, tremor, profuse sweating, nightmares/insomnia, headache, anxiety, irritability, feelings of emptiness, depressive symptoms, and somatic complaints [102]. However, little has been published on the prevalence or natural history of cannabimimetic use disorder [154].

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 [156]. 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. With assessment of patients acknowledging drug use-related problems, invite active patient contribution by asking open-ended questions, such as: