#96912: Novel Psychoactive Substances: Trends in Drug Abuse

Record of chemical name by year was once an effective way to track changes in cathinone and amphetamine derivative generations [23]. However, the quick pace at which chemicals structures are altered to create newer versions of drugs in order to circumvent drug laws eventually made it reasonable to change the system of classification of these derivatives.

Because of the rapid changes to this class of synthetic drug and because several drugs are no longer prevalent, today many researchers and law enforcement personnel refer to the chemical makeup rather than year to track changes in NSP. Although there is no standard international nomenclature among different agencies, cathinone derivatives have been categorized into four groups by chemical structure, with novel drugs being created by slightly altering each structure [163]:

As noted, the NPS arena is characterized by an evolutionary "arms race" between manufacturers and regulators. The U.S. Drug Enforcement Administration (DEA) broadens prohibition of NPS agents and structures, with manufacturers introducing NPS that circumvent these legislative actions. The hazard from this process is that manufacturer efforts to circumvent new drug laws will lead to NPS entry with greater toxicity and morbidity risk, as already observed with fluorinated cannabimimetics and likely with synthetic cathinones and other NPS [25,28].

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 unfolded in the United Kingdom (UK) during the 2000s with the NPS mephedrone and MDPV, and in 2012 the United States followed trend with the enactment of the Synthetic Drug Abuse Prevention Act and subsequent decline in use [17,24].

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 [26]. This is an ongoing process, and the most recent list of temporary and permanent NPS placed in Schedule I is found on the DEA website at https://www.deadiversion.usdoj.gov/schedules.

Other attempts at regulating NPS are still being developed. The UK responded to emerging NPS by enacting the European Psychoactive Substances Act of 2016, making it illegal to produce or supply many drugs including NPS. Though more research is needed, one survey showed a modest put positive reduction in the online availability of MDMB-CHMICA (from 47 to 38 websites offering the substance) one month after implementation of the Act. Some websites removed information indicating they were based in the UK, three stated that they could no longer supply customers in the UK, and two websites specifically referred to the Act [162]. 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. As noted, in July 2021, HB 4459: SIMSA Act of 2021 was reintroduced as a result of increased drug overdoses in 2019 and 2020 [33,89]. In addition, many individual states have enacted legislation to regulate the distribution and use of NPS [54].

Rapidly spreading local/regional outbreaks of NPS use, toxicity/overdose requiring emergency medical services (EMS), and fatalities all increased through 2014 and 2015 (Table 2). Especially hard-hit were Broward County, Florida, with county hospitals averaging 20 emergency department admits per day for alpha-PVP overdose or excited delirium, and Washington, DC, where cannabimimetic toxicity led to 439 emergency department admits in one month. Many DC toxicities were excited delirium; two homicides were committed during cannabimimetic-induced excited delirium, with one victim stabbed 40 times on a subway [19,31].

Reports to the network of 55 poison control centers in the United States provide 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, although 2011 shows the highest rates combined for the two categories (Table 3) [36].

It should be noted, beginning in 2013, poison control call counts are lower than actual NPS toxicities, as emergency department staff has become increasingly adept in identifying and managing NPS toxicity [19].

Current NPS exposure report data are available at https://www.poison.org/poison-statistics-national.

From the peak of past-year use in 2011–2012, cannabimimetic use has declined among adolescents and young adults (Table 4). For example, among 12th graders, 11.3% used synthetic marijuana, decreasing to 3.3% in 2020 [36]. The same trends have followed among 10th and 8th grade students [39]. This decline likely reflects the greater numbers of identified and banned NPS and/or an increase in the perception of harm [39,47]. High school and college students and adults 19 to 30 years of age have indicated an increased perception of risk of trying synthetic marijuana once or twice, with an average of 29.5% in 2012 to 43.9% in 2020. In both years, the perceived risk was higher if using synthetic marijuana occasionally (versus once or twice), with 37.4% in 2012 and 52.4% in 2020 [39].

Cathinone use has also declined since 2012, although not as dramatically as users of cannabimimetics, given the overall lower usage rate (>1% annually). Very high rates of perceived danger from even single-use synthetic cathinones may explain the lower rates, with rates of perceived risk of 45% to 49% in 2012, compared with 68% to 72% in 2017 [39]. As of 2019, questions regarding cathinones has been removed from the annual National Survey Results on Drug Use study to study other emerging drugs [36].

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].

Military Personnel

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].

Persons on Probation/Parole

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.

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]. Drug testing groups have begun to sneak equipment past security to provide services, but violent retaliation by drug dealers is an ongoing concern [25].

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].

A 2010 survey of mephedrone users in London found that use of this drug was intended to augment, but not replace, pre-established use patterns of cocaine, Ecstasy, and MDMA. This pattern increases the risks of drug interaction toxicities in users [45].

Importantly, data suggest polysubstance use may be more or less prevalent in users of specific NPS, rather than endemic. Several studies found significantly higher rates of mono-substance use in cannabimimetic-related emergency department admissions than in patients with synthetic cathinone-related admissions. This may importantly influence management of patients with acute NPS toxicity [40].

There are 27 known 2C compounds, all originally produced by Alexander Shulgin. The powerful hallucinogen 2C-B was the first 2C synthesized, in 1974, by simple alterations to the natural phenylethylamine molecule mescaline [47]. The more commonly encountered 2Cs in the United States are 2C-B, 2C-I, and 2C-T-7, known by the street names Nexus, Bromo, Blue Mystic, and T7.

The effect following oral use in the lower dose range (<8 mg for 2C-B, 3–25 mg for 2C-I, 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 [51,52,53].

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 [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].

The 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 [56]. They are commonly known by the street names N-Bomb, Smiles, 25I, 25C, and 25B.

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 [56].

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 [57,58]. 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 [59].

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 [56]. Even small amounts can cause seizures, cardiac and respiratory arrest, and death [57]. Many fatalities have occurred following NBOMe use, typically preceded by excited delirium [60,61].

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 analogue of 5-APB [62].

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 [62].

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].

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 [63].

Aminoindanes were first synthesized in the 1970s and investigated for their significant bronchodilating and analgesic properties, though they were later found to produce psychoactive effects. Aminoindanes are amphetamine analogs, with their molecule characterized by a closed five-membered ring system next to the parent six-membered system. This configuration bestows minimal to no neurotoxicity (in preclinical studies) and higher serotonin than dopamine activation (which dampens drug craving). Together with Internet availability as "research chemicals," these actions form the basis of predictions that aminoindanes will become the next wave of NPS [64,65].

2-Aminoindane (2-AI) produces a stimulant effect similar to amphetamine but at one-sixth the potency. It also induces an analgesic effect that, in contrast to morphine, does not depress the brain respiratory center and is not counteracted by nalorphine. In contrast to amphetamines, 2-AI does not increase motor activity but does decrease food consumption. 5-Methoxy-6-methyl-2-aminoindane (MMAI) is a potent serotonin releaser but minimally inhibits dopamine uptake. By stimulating serotonergic neurotransmission, it can increase secretion of hormones such as adrenocorticotropic hormone. Compared with MDMA, 5-IAI is a greater serotonin and dopamine releaser and minimally inhibits their reuptake. Both are non-neurotoxic [66,67]. Some 1-AIs are promising candidates for psychosis treatment, and the substituted derivative rasagiline is used in the treatment for Parkinson disease [64,68]. The finding of potent 5-HT2B receptor full agonist activity with 5-IAI suggests cardiotoxic potential with long-term use, as this mechanism is shared by all drugs that induce heart valvular disease in humans, including fenfluramine, MDMA, and various ergolines [69].

Following oral ingestion of powder or crystals, aminoindanes produce empathogenic and entactogenic effects similar to other serotonin-releasing drugs (such as MDMA) and a mild stimulant effect similar to amphetamine [70].

The pipradrol derivatives diphenylprolinol (D2PM) and desoxypipradrol (2-DPMP) are selective and very potent monoamine transporter inhibitors without substrate-releasing properties. This pharmacologic profile closely resembles MDPV and alpha-PVP and predicts high risk of abuse potential and psychiatric morbidity. First appearing in 2010 as "Ivory Wave," clinical toxicity from 2-DPMP/D2PM is long-lasting (24 to 72 hours), with sympathomimetic symptoms of hypertension, agitation, and hallucinations [8].

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 [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 [8].

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 [46,81].

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 [17,82]. 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 [8,82].

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].

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 [46,83].

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 [84].

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 [85].

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 [85].

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 [46,83].

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 [46,83].

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 [46,83,85].

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 [8,14].

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 [8].

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 [1]. 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 [86,87,88].

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].

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 [90]. 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 [16,91].

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 [16].

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 the 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 [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].

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 [97]. 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 [98]. 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" [98]. 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 [98].

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 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 [77].

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 [99]. 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 [73]. 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 [77,100].

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].

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 [127,128]. 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 [129,130].

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 [77,131].

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 [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].

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 [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% [48,136].

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 [136].

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.

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 [93,142].

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 [93,143].

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 [93,144].

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 [93]. 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.

Anticholinergic toxidromes can resemble NPS toxicity, with altered consciousness, agitation, confusion, disorientation, delirium, hallucinations, tachycardia, tachypnea, and hyperthermia [145]. Sympathomimetic toxidrome may be differentiated from anticholinergic toxidromes by presence of marked diaphoresis (instead of dry skin) and lack of bowel sounds [145]. The presence of neuromuscular abnormalities is specific to serotonin syndrome and is not seen in patients with anticholinergic toxidromes.

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].

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 [149].

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 [106]. Antipyretics are ineffective for hyperthermia because the origin is increased muscular activity, not hypothalamic temperature dysregulation [149].

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 [93]. Fatalities following cannabimimetic use have occurred in patients discharged home with lingering paranoia and depression [50].

The abuse potential of synthetic cathinones can be predicted by pharmacologic activity. The ratio of dopamine to serotonin increase influences episodic (i.e., recreational) versus compulsive (i.e., addictive) use patterns [9]. Cathinones release more dopamine than serotonin (similar to methamphetamine and cocaine), which predicts drug craving, urge to re-dose, and addiction liability [76]. Drugs that release higher serotonin than dopamine levels (e.g., MDMA) tend to have a dampening effect on craving and urge to re-dose and a lower abuse potential [74,75].

A survey of 1,500 mephedrone users found more than 50% considered it addictive [150]. Of 1,006 students older than 21 years of age in Scotland, 4.4% were daily mephedrone users and 17.5% of users reported addiction/dependence symptoms [151]. In a study of 100 British mephedrone users, 47% had binged on mephedrone, 30% met Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria for mephedrone dependence, and 44% described mephedrone as at least as addictive as cocaine [92]. More than 50% developed tolerance after continued use and described withdrawal symptoms of tiredness, difficulty concentrating, depression/anxiety, irritability, and ongoing cravings for mephedrone [92]. Another study found that 22.4% of mephedrone users experienced intense cravings when they stopped [152].

Frequent high-dose methcathinone, mephedrone, and MDPV use induces tolerance, dependence, craving, and a withdrawal syndrome with cessation characterized by depression, anxiety, sleep disorders, and fatigue, with craving, anhedonia, and anergia that can last several weeks [153]. Class-wide, cathinone withdrawal symptoms include depression, impulsivity, anhedonia, and cognitive complaints of poor concentration and attention [18].

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].

The abuse liability of many other NPS is anecdotal, and while pharmacologic profiles can help predict risks of craving and compulsive use (as discussed), little is known of the prevalence, natural history, or withdrawal syndromes in patients with heavy/prolonged use [3].

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, with many stating they will not enroll in such services [25]. However, specialized NPS treatment programs in the UK report high demand and offer specialist assessments, detoxification, psychologic and psychosocial treatment, and support/referral for drug-related health problems [25,155].

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 [25,61]. Patients identified with NPS use disorder in the emergency department or inpatient setting should be linked to information on local addiction treatment resources (Table 7) [61].

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 [61].

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:

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 [156].

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 [61]. Encouragement of 12-step program involvement, such as Narcotics Anonymous, can provide patients the means for support, a non-substance-using social network, and other benefits conducive to recovery.

Bupropion

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 [157,158].