The Illicit Drug Market: A Clinical Primer 2023

Polysubstance and Illicit Substance Use Continue to Rise

Drug-related overdose deaths have continued to climb over the past decade, while the United States struggles to combat the harsh reality of the new phase of the overdose crisis. One particular concern of this phase is that overdose deaths appear to be primarily driven by illicitly manufactured fentanyl analogues, which have flooded the illicit substance market, as well as polysubstance use.¹

Herein, we review the most commonly used NPS – novel synthetic opioids, psychedelics, and cocaine – including specific types used, trends, ­­clinical features, and potential toxicities/interactions:

In the past 10 years, novel synthetic opioids (NSOs) have become an emerging class among novel psychoactive substances.² Illicitly manufactured fentanyl analogues have largely driven this class of NPS, but several other emerging non-fentanyl classes of NSOs, including nitazenes, are also at play.²⁻³

The chemical structure of NSOs varies depending on the individual compound, however, all NSOs modulate the opioid receptor system (by agonizing mu-opioid receptors), and may be used as standalone products, adulterants in other substances, or constituents in illicitly manufactured drugs.²⁻³

In order for NSOs to be considered “fentanyl-related substances,” the chemical must be structurally related to fentanyl, maintaining its piperidine base structure.⁴ There have been hundreds of fentanyl analogues identified to date, and while an in-depth comparison between them is beyond the scope of this article (see: Fentanyl: Separating Fact from Fiction), it is important to note that there is a paucity of data on the vast majority of these compounds; particularly regarding relative potency.⁵⁻⁶ The majority of available pharmacodynamic data appears to be on acetylfentanyl, butyrfentanyl, ocfentanil, 3-methylfentanyl, ohmefentanyl, and acrylfentanyl, which range in relative potency between 3 and 6,300 to 1 compared to morphine.⁵⁻⁶

Carfentanil is interesting, as it has garnered much attention in the past few years with regard to its role in the overdose crisis.⁵⁻⁶ Technically, it is considered a pharmaceutical fentanyl derivative, as it is approved for use in animals, however, the drug is not approved for use in humans.⁵⁻⁷ The danger with carfentanil is that it is approximately 10,000 times more potent than morphine, and its presence in the illicit drug supply has increased, often laced with heroin, leading to hundreds, if not thousands of opioid-related deaths.⁵⁻⁸

In addition to the rise of fentanyl-related synthetic opioids, non-fentanyl synthetic opioids have also expanded in the illicit substance market. Some of these include benzamides (AH-7921), piperazines (MT-45), and nitazenes, all of which have atypical chemical structures and varying potencies.²˒⁷ For example, AH-7921 has been found to be about 0.8 times as potent as morphine, where MT-45 has a potency closer to morphine.⁷˒⁹ Nitazenes (isotonitazene and metonitazene) are an entirely different class of MOR agonists originally developed by pharmaceutical companies in the 1950s – this class never achieved FDA approval for use in humans.¹⁰ Like other NSOs, nitazenes are potent, come in various dosage forms, and may be specifically sought or may be found as adulterants in the illicit substance supply.¹⁰

Causes for Concern: Respiratory and Muscle Rigidity Effects

The increasing presence of illegal yet accessible NSOs could lead to an increase in accidental overdoses.¹¹ Not only do respiratory depressive effects occur more quickly with these substances, but also, high potency opioids are associated with induction of muscle rigidity (specifically chest wall rigidity), which increases difficulty of assisted ventilation attempts.¹² The potency and longer-acting nature of NSOs may also require repeated doses of naloxone, an opioid receptor antagonist, to effectively reverse overdoses, and may require continuous administration to outlast NSOs potentially longer half-lives.¹¹˒¹³

Phenethylamine

Phenethylamine refers to the base structure of a class of substances with psychostimulant and hallucinogenic effects inclusive of amphetamines and amphetamine-like drugs such as methamphetamine, 3,4-methylenedioxy-methamphetamine (MDMA, aka “ecstasy”), cathinones, and benzodifurans, among others. Mescaline, a chemical isolated from the peyote cactus, is considered the prototypical phenethylamine compound from which a majority of phenethylamine psychedelics are derived.¹⁵ While there are significant differences in chemical structure between the varying subclasses of phenethylamines, all of them exert their activity through sympathomimetic, dopaminergic, serotonergic, and noradrenergic effects.¹⁵

Amphetamine and Methamphetamine

Both amphetamine and methamphetamine are available as FDA-approved products and formulations for varying types of attention deficit-hyperactivity disorder (ADHD) and, as short-term use for weight loss, although both are frequently misused as well.¹⁷˒¹⁸ Methamphetamine specifically dominates the prevalence of trafficking and use of the amphetamine stimulant class worldwide and in the US.¹⁶ Its dominance can be attributed to the relative ease with which it is able to be manufactured and produced.¹⁶ The smoked, crystalline form of methamphetamine (“crystal meth”) also tends to be preferred over its oral formulation due to its ability to produce very rapid and intense “high” effects, as smoking allows for bioavailability to reach about 80% to 95%.¹⁹

Because of these mechanisms, both amphetamine and methamphetamine are associated with enhancing alertness, increasing concentration and energy, elevating feelings of euphoria (usually at higher doses), and suppressing appetite.²⁴˒²⁵ However, they also may induce manic symptoms, hallucinations, delusional thinking, and aggression, both in the acute phase and with chronic use.²⁴˒²⁵

Further, both substances activate the cardiovascular system through their significant noradrenergic activity, which can lead to systemic increases in blood pressure and heart rate, and is what may lead to death if higher doses are used (or if used in intolerant patients).²⁴˒²⁵ Risk of sudden cardiac death increases in those with structural cardiac abnormalities or other serious heart problems.¹⁷˒¹⁸ Finally, because of their inhibition of monoamine oxidase, their use with other medications with serotonergic activity can increase the risk of serotonin syndrome and potential for seizure induction.²⁴˒²⁵

MDMA

MDMA is a compound initially experimented on throughout the 1960s and 1970s, coinciding with a rise in curiosity about psychedelics effects, both therapeutic and recreational.²⁶ Therapeutic use of MDMA rose in the 1980s to treat a wide variety of psychiatric conditions, however non-clinical use of the drug spread as well, often under the street name “ecstasy.”²⁶

While MDMA’s chemical structure is similar to other amphetamine-type stimulants, and thus has similar mechanisms, there are some key differences. One difference is that MDMA principally modulates the release of serotonin and norepinephrine, and modulates dopamine to a lesser degree.²⁸˒²⁹ It has also been shown to modulate 5-HT1A and 5-HT1B receptors, which may explain its association with attenuating feelings of depression and anxiety, reducing the fear response, and enhancing self-confidence.²⁸˒²⁹ In addition to its norepinephrine activity, MDMA works at alpha-2 receptors, which may explain its cardiovascular and thermogenic response, as well as facilitates the release of oxytocin, which may add to its overall entactogenic effects.²⁸⁻³⁰

Causes for Concern: Cognitive, Cardiovascular and Serotonergic Effects

There can be a variety of adverse effects, especially cognitive, associated with MDMA use. These include spatial memory deficits, slower processing speeds, executive functioning impairments, poor concentration, and impaired balance, all of which may occur acutely or with chronic use.³³˒³⁴ Because of its noradrenergic profile, MDMA use also may lead to increased blood pressure, heart rate, and body temperature, adding concern in those with underlying cardiovascular/heart problems.³³˒³⁴ Further, low mood in between doses is a relatively common side effect.³³˒³⁴ Similar to other stimulant-type chemicals, serotonin syndrome and seizure risk may increase with concomitant use of medications with serotonergic activity.³³˒³⁴ What is of significant concern is that there has been increasing prevalence of different substances found in ecstasy-labeled products, such as MDA, MDEA, and even novel psychedelics.¹⁶

In addition to the more traditional phenethylamine stimulants, derivatives have entered the illicit substance market, some with an N-(2-methoxybenzyl) phenethylamine chemical backbone.¹⁵˒¹⁶ These are known as the NBOMes, and are commonly referred to as “N-bomb” or “Pandora.”¹⁵˒¹⁶ Similar to the classic amphetamine-type stimulants, NBOMes have shown to be associated with higher rates of addiction compared to MDMA due to differences in mechanism and potency.¹⁵˒¹⁶

A primary difference is that the NBOMes potently agonize 5-HT2A and 5-HT2C receptors, which allows them to more frequently produce hallucinations and delusions.¹⁵˒³⁵ This potency allows for miniscule amounts to be used, and they are often sold as LSD replacements, or added to other psychedelics to enhance effects.¹⁵˒³⁵

Causes for Concern: Cardiovascular, Agitation, and Seizure Risk

Unfortunately, they too are highly associated with activation of the cardiovascular system (tachycardia, hypertension), enhancing agitation, and may significantly increase risk of seizures (especially when combined with medications that lower the seizure threshold).¹⁵˒³⁵ An increasing number of fatalities from this class of drug use have been described.¹⁵˒³⁵

Cathinones (aka “bath salts”) are in another chemical subclass that falls under the phenethylamine umbrella and are inclusive of several “classic” substances, including amfepramone, cathine, cathinone, mephedrone, and methcathinone.³⁶ Even within this class, there has been an increasing presence of novel synthetics infiltrating the illicit market including 4-methylethcathinone, alpha-pyrrolidinopentiophenone (PVP), and flephedrone.³⁶

Traditionally, cathinones have been placed in three categories based on mechanism.³⁷ The first category contains cathinones that act as substrates of dopamine, serotonin, and norepinephrine transporters, thus acting more like MDMA (eg, mephedrone, methylone, butylone, etc.).³⁷ The second category includes cathinones that more selectively act as substrates to dopamine transporters, thus producing similar effects as amphetamine and methamphetamine (eg, cathinone, methcathinone, and flephedrone).³⁷ The third category includes those that do not act as substrates of monoamine transporters at all, but actually inhibit the reuptake of selective monoamines (or all of them).³⁷ For example, 3,4-methylenedioxypyrovalerone (MDPV) inhibits the uptake of dopamine, serotonin, and norepinephrine, and thus acts similar to cocaine.³⁷

Causes for Concern: Behavioral, Cognitive, Cardiovascular and Dependence Effects

Cathinones are commonly associated with problematic behavioral and cognitive side effects, including agitation that may lead to severe psychosis, as well as restlessness, anxiety, and paranoia.³⁶˒³⁹ Additionally, they can be associated with significant cardiovascular effects including hypertension, tachycardia, chills, sweating, and flushing.³⁶˒³⁹ The most severe side effects include renal failure, rhabdomyolysis, induction of seizures, and significant mood disturbances.³⁶˒³⁹ Unlike MDMA, cathinones are more greatly associated with the development of tolerance, dependence, and addiction.³⁶˒³⁹

Ketamine is an arylcyclohexylamine that was synthesized from phencyclidine (PCP, see below) in 1956 by the Parke Davis Company, and initially studied throughout the 1960s.⁴⁰ It was eventually approved by the FDA four years later under the brand name Ketalar for pre-induction anesthesia.⁴¹ Since that time, ketamine has been studied in a variety of dosage forms to treat several pain and psychiatric conditions, with increasing use both pharmaceutically and illicitly (though, illicit use may be decreasing with expansion of pharmaceutical use over the past decade).¹⁶

The majority of ketamine’s primary dissociative and hallucinogenic activity stems from its ability to non-competitively antagonize N-methyl-D-aspartate (NMDA) receptors throughout the CNS via allosteric open-channel blockade.⁴²˒⁴³ This allows for a relatively slow “off-rate,” which is one characteristic that distinguishes ketamine’s physiologic effects from other compounds that inhibit NMDA receptors.⁴²˒⁴³ Ketamine also antagonizes alpha-amino-3-hydroxy5-methylisoxazole-4-propionic acid (AMPA) receptors, antagonizes L-type calcium channels, increases the release of various aminergic neuromodulators including dopamine and noradrenaline, reduces cholinergic neuromodulation, and augments delta- and mu-opioid receptor function.⁴²˒⁴³

Causes for Concern: Dose-Dependent Effects

While there have not been as many novel synthetic ketamine compounds that have emerged over the past 20 years, there has been rising controversy with the increased use of it medically in conditions often without supportive clinical evidence nor appropriate clinical monitoring.¹⁶˒⁴⁶ In fact, standard of care can vary widely between ketamine treatment centers because of the lack of well-defined guidelines and use often by those inexperienced with ketamine therapy in.¹⁶˒⁴⁶ This is particularly concerning given ketamine’s dose-dependent effects and potential for significant adverse reactions.

Phencyclidine (PCP, “angel dust”) is a chemical similar to ketamine that was originally developed as a pre-induction anesthetic for both human and animal use.⁴⁷˒⁴⁸ However, because of its potent dissociative and hallucinogenic effects, as well as its ability to produce delirium, research was discontinued in the early 1960s.⁴⁷˒⁴⁸ Its use has wavered in the past decades.¹⁶˒⁴⁹ Inhalation of its base form (a crystalline powder) remains the most common type of usage mainly because of its rapid onset of action (within 2 to 5 minutes) compared to oral ingestion, and minimizes complications that are often seen with injection of the liquid formulation.⁵⁰

Mechanistically, PCP targets several different sites throughout the CNS. Like ketamine, at low doses, PCP is an NMDA receptor antagonist, but works non-competitively at the PCP-binding site.⁴⁷⁻⁴⁹ As doses escalate, PCP begins to inhibit the reuptake of dopamine, norepinephrine, and serotonin, and stimulates tyrosine hydroxylase intracellularly leading to increased dopamine and norepinephrine production.⁴⁷⁻⁴⁹ Its activity on NMDA receptors, and the glutamatergic complex as a whole, is generally what allows for its dissociative and hallucinogenic effects, in that it is commonly used to produce dissociation from the environment, out-of-body experiences, and intense hallucinations.⁴⁷⁻⁴⁹

However, these experiences can lead to acute cognitive side effects including memory impairment, altered perception of reality, anxiety, psychosis, stupor, and even sporadic violent behavior.⁵¹˒⁵² Higher doses may lead to coma unresponsive to deep pain stimuli, seizures, cerebrovascular accidents, cardiac arrest, and/or death.⁵³ Chronic and long-term use of PCP may lead to longer-term impairment of memory and thinking, suicidal ideation and behavior, and physical dependence.⁴⁸

Tryptamines (Psilocybin, DMT)

The tryptamine class of psychedelics includes those that act as monoamine alkaloids, exerting similar activity as endogenous serotonin (5-hydroxytryptamine or 5-HT).¹⁵˒⁵⁴ These chemicals are both found in nature and are created synthetically.¹⁵˒⁵⁴ The traditional tryptamines found in nature include dimethyltryptamine (DMT) that comes from the Delosperma genus of plants, bufotenine extracted from certain amphibians, and specific fungi, such as psilocybin mushrooms.¹⁵˒⁵⁴

Given tryptamines in general act as endogenous serotonin, they are known to specifically agonize 5-HT1A, 5HT2A, and 5HT2C receptors with varying potencies and affinities.¹⁵˒⁵⁵ They also agonize VMAT-2 and alpha-1 adrenergic receptors, and modulate serotonin reuptake transporters and traceamine-associated receptors.¹⁵˒⁵⁵ All of these mechanisms, to varying degrees, allow users of tryptamines to experience visual hallucinations, sensory perception alterations, entheogenic experiences, distortion of own self, mood lability, and euphoria.⁵⁴˒⁵⁶ Side effects, usually more so associated with acute use, may include anxiety/panic, agitation, tachyarrhythmia, and hyperpyrexia.⁵⁷

DMT and psilocybin are interesting in additional ways. DMT is inactive when taken orally but activates when combined with monoamine oxidase inhibitors (MAOi), which is why ayahuasca is commonly used with it (ayahuasca is a MAOi).¹⁵˒⁵⁴ Further, DMT has particularly potent hallucinatory and euphoric effects.⁵⁴

Psilocybin acts slightly differently than other tryptamine psychedelics, as it is a partial agonist at 5-HT2A with reduced dopaminergic and noradrenergic activity.¹⁵˒⁵⁷ When lower doses are used, similar effects as other tryptamines are seen; at higher doses, strong dysphoria as well as anxiety and/or panic are more commonly reported.⁵⁶ Further, transient headaches are also common with use.⁵⁸

Lysergic Acid Diethylamide (LSD)

The lysergic acid diethylamide (LSD) of today is an entirely different psychedelic than that synthesized accidentally by Albert Hofmann in 1938 while experimenting with substances from ergot derivatives, all in an attempt to create a novel stimulant.⁵⁹ The chemical he ended up creating had a structural backbone shared by both tryptamines and phenethylamines, which likely helped explain its complex behavioral and pharmacologic effects.⁵⁹ Interest in LSD-assisted therapy peaked in the 1960s and 1970s, as it was studied for a variety of neuropsychiatric disease states including depressive disorder, mania, psychoneurotic disorders, schizophrenia, borderline, personality disorders, among others, though never achieved FDA approved status in the US.⁵⁹

The primary mechanisms of LSD include activating 5HT2A, 5HT2B, and 5HT1A receptors, partially agonizing 5HT2C receptors, as well as affecting the expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor; though it is unclear what overall role the latter mechanisms play in its clinical effects.⁶² LSD is often used recreationally to cause hallucinations, perceptual disturbances, synesthesia, and distortions of reality and time.⁶² It is also relatively common for users to experience “bad trips,” where unpleasant, or even terrifying, experiences are reported. Further, recurrence of drug-induced experiences (so called “flashbacks”) are well described as well, which can occur without warning, though may be induced by stress or fatigue.⁶² Other physiological effects include tachycardia, hypertension, dilated pupils, and elevated body temperature.⁶²

Causes for Concern: Potency and Onset

Similar to other illicit substances used, there have been novel LSD derivatives that have emerged over the past decade. Some of these include lysergic acid 2,4-dimethylazetide (LSZ), 1-propionyl-d-lysergic acid diethylamide hemitartrate (1-P-LSD), and 6-allyl-6-nor-lysergic acid diethylamide (AL-LAD).¹⁶ Usually, these derivatives have similar mechanisms, however they differ in potency, duration, and onset of action.¹⁶

While cocaine is certainly not a novel substance by any measure, interestingly, its manufacturing was at a record high in 2020 globally, growing by 11% since 2019.¹⁶ Overall trafficking and use of cocaine continue to increase as well.¹⁶

Cocaine is a tropane alkaloid extracted from the leaves of the Andean shrub (Erythroxylum coca) throughout South America, and it is one product among many that have been derived from that species of plant and used for thousands of years.¹⁶˒³⁶ Cocaine products can differ in myriad ways, often determined by geographical location. The first difference comes down to its chemical nature which has two main forms: a base (ie, coca paste) or a salt (hydrochloride salt of cocaine).¹⁶ The second difference has to do with additives and constituents that may be added to the product.¹⁶ The vast majority of users consume cocaine in its salt form (often powder), however, there can be differences in the onset of effect and even experience depending on the form used.¹⁶

Besides the continued rise in use of traditional cocaine products, several novel synthetic cocaine derivatives have emerged over the past decades as well. Two of these are dimethocaine and 4-flurotropacocaine (pFBT).¹⁶˒³⁶ Both are mechanistically similar to cocaine, however appear to inhibit the reuptake of dopamine rather selectively, changing some of their behavioral effects and overall adverse effect profile.¹⁶˒³⁶ Additionally, like other cocaine products, they are usually sold in their powder form to be insufflated or combined with liquid to be injected, as ingestion allows for rapid hydrolysis within the digestive system.

The adverse effects of cocaine are well known and quite common, especially cardiovascular, including peripheral vasoconstriction, tachycardia, hypertension, and increased body temperature.⁶⁶ It can be associated with increased anxiety, erratic behavior, irritability, and paranoia.⁶⁵ There can be severe cardiovascular complications associated with cocaine use as well including arrhythmias and myocardial infarction, while chronic cocaine use can lead to cardiomyopathy, coronary artery disease, strokes, and seizures.⁶⁷ Cocaine use with other illicit and FDA-approved substances can be dangerous (especially ones with serotonergic and noradrenergic activity), but combined use with alcohol can be particularly dangerous due the creation of cocaethylene, which can potentiate the toxic effects of both on the heart.⁶⁷

As the US and many parts of the world continue to suffer from a worsening overdose crisis at a magnitude not seen before, there has been increasing concern about the quality of the illicit substance market and the emergence of NPS across all chemical classes. These include novel synthetic opioids, novel phenethylamines, novel psychedelics, and novel cocaine derivatives, all of which often possess greater potencies, exhibit varying pharmacologic effects, and are associated with increasing mortality.