A unique trend in recreational and problematic drug use began to emerge in the United States around 2008, with the introduction and proliferation of previously unknown or unavailable psychoactive substances. By 2015, this trend became an established element of domestic and global recreational drug cultures, and nearly two decades later is the center of a global drug crisis. The United Nations Office for Drug and Crime (UNODC) defines novel or new psychoactive substances (NPS) as "a substance of abuse, either in a pure form or a preparation, that are not controlled by the 1961 Single Convention on Narcotic Drugs or the 1971 Convention on Psychotropic Substances, but which may pose a public health threat" [1]. The use of the word "new" or "novel" does not necessarily refer to the invention of a new drug, but rather indicates a substance has emerged or re-emerged as a psychoactive substance or synthetic drug of abuse. NPS often have similar molecular structures as controlled or banned substances but are slightly modified by manufacturing and/or trafficking organizations with intent to circumvent existing drug laws [1,12].

Concurrently, the interception of cocaine shipments into Europe from South America made cocaine scarce and poor in quality. The European emergence of cathinones in the early to mid-2000s filled the void of MDMA and cocaine by promising users a legal-high substitute. Cathinones began replacing MDMA in Ecstasy and were introduced as over-the-counter "bath salt" products. The decreasing MDMA content in Ecstasy coincided with the 2009 emergence of cathinones in the United States, which were promoted as less expensive "legal high" ecstasy and cocaine alternatives [3].

The Internet is the predominant marketplace for NPS and plays an essential role in the NPS phenomenon through a variety of mechanisms. NPS users and manufacturers are able to utilize the Internet for information on acquisition, synthesis, extraction, identification, and use of these substances. The Internet also serves as the marketplace that connects manufacturers, suppliers, retailers, and end users. It is increasingly common that manufacturers, suppliers, retailers, web-hosting, and payment processing services are based in different countries, and this decentralization of the online drug markets adds to the difficulty for law enforcement control [1,3,12].

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].

An astonishing diversity of structural families and subgroups of NPS and psychoactive drugs have been synthesized from the single parent molecule phenethylamine. Phenethylamines are a broad molecular class that can produce both hallucinogenic and stimulant effects. Phenethylamines fall into three sub-families: ring-substituted phenethylamines, amphetamines, and methylenedioxyphenethylamines. More than 180 phenethylamines have been reported to the UNODC, the majority of which are ring-substituted [1,8]. For the purposes of this course, phenethylamines (plural) refers to phenethylamine derivatives as a category.

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].

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. 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 [45,46].

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 [18,45,46].

Natural cannabis and cannabimimetics overlap mechanistically through CB1 receptor binding and activation to produce the shared subjective effects of relaxation, euphoria, perceptual changes (e.g., altered sense of time, intensified sensory experiences), cognitive impairment (e.g., amnestic symptoms, slowed reaction time), and the physiologic effects of xerostomia, conjunctival injection, and tachycardia. Acute changes in mood, anxiety, perception, thinking, memory, and attention are common to both. Agitation, aggression, paranoia, anxiety, and psychoses are common with cannabimimetic use and less common or rare with cannabis use. As discussed, the more frequent and severe psychosis, agitation, and sympathomimetic effects with cannabimimetic use reflect greater potency, full CB1 agonist action, and absence of CBD [1,8,45].

Tryptamines are monoamine alkaloids synthesized by decarboxylation of tryptophan and are quite varied. They include natural neurotransmitters (e.g., serotonin, melatonin); hallucinogens found in plants, fungi, and animals (dimethyltryptamine [DMT], 5-MeO-DMT, bufotenin); synthetic pharmaceutical products (e.g., sumatriptan and zolmitriptan to treat migraine); and various synthetic hallucinogenic compounds, such as alpha-methyltryptamine (AMT), diisopropyltryptamine (DiPT), 5-MeO-DiPT, 5-MeO-AMT, diethyltryptamine (DET), and 5-MeO-DET [1; 8]. Use of tryptamines for psychoactive effect began in the late 1950s with psilocybin, the natural ingredient in certain mushroom species. Synthetic tryptamines appeared on the illicit drug market in the United States during the 1990s .

More than 60 individual tryptamine NPS have been reported to the UNODC. Tryptamines have an indole ring structure (a fused pyrrole and benzene double-ring) joined to an amino group by a 2-carbon side chain. Psychoactive effects are closely related to their structural influence on receptor affinity. Tryptamines produce dominant hallucinogenic/psychedelic effects as 5-HT2A/1A/2C receptor agonists. Alpha methylation leads to stimulant activity, as with AMT and 5-MeO-AMT. Many synthetic tryptamines are monoamine releasers, increasing the risks of serotonin syndrome and sympathomimetic toxicity. With primarily serotonergic action, tryptamines lack reinforcement and abuse liability. NPA tryptamines are grouped by structure into three categories: indole ring-unsubstituted tryptamines, 4-position ring-substituted tryptamines (e.g., psilocybin), and 5-position ring-substituted tryptamines.

Mitragynine is the primary active alkaloid of kratom. Kratom leaves are ingested by chewing or boiling into tea. The effects last two to five hours. Low doses produce increased alertness, physical energy, talkativeness, and sociable behavior. High doses produce an opioid-like effect with sedation and euphoria. Undesired effects include nausea, itching, sweating, dry mouth, constipation, increased urination, and loss of appetite [49].

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].

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].

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].

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.

The abuse potential of synthetic cathinones and other opioid receptor agonists can be predicted by pharmacologic activity. The ratio of dopamine to serotonin influences episodic (i.e., recreational) versus compulsive (i.e., addictive) use patterns. Cathinones release more dopamine than serotonin (similar to methamphetamine and cocaine), which predicts drug craving, urge to re-dose, and addiction liability. 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 [1,58]. Frequent high-dose opioid 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. Class-wide, withdrawal symptoms include depression, impulsivity, anhedonia, and cognitive complaints of poor concentration and attention [18].

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].

Harm reduction neither condones nor condemns drug use, but instead recognizes that some risks from recreational NPS use can be mitigated. DanceSafe is the largest harm-reduction organization for North American nightlife/electronic dance music communities. Efforts by DanceSafe are directed at non-addicted recreational users, who comprise the largest number of drug users but are underserved by conventional harm reduction that targets addicted users. DanceSafe objectives include reducing drug misuse and empowering users to make informed decisions about their health and safety by providing unbiased educational literature on the effects/risks of specific drugs; remote and, when possible, on-site adulterant screening (drug testing); on-site free water and electrolytes to help prevent hyperthermia; free ear plugs; free safe sex tools to avoid pregnancy and sexually transmitted infections; and first point of contact for adverse drug effects [52]. Many other American and European harm-reduction groups use common objectives and methods.