Twenty-First Century Illicit Drugs and Their Discontents: The Challenges Posed by Novel Psychoactive Substances (NPSs)

Special Report Crime and Justice

Twenty-First Century Illicit Drugs and Their Discontents: The Challenges Posed by Novel Psychoactive Substances (NPSs)

May 17, 2024 Over an hour read Download Report
Paul Larkin
Rumpel Senior Legal Research Fellow
Paul is a Senior Legal Research Fellow in the Meese Center for Legal and Judicial Studies at The Heritage Foundation.


Novel Psychoactive Substances multiply the difficulties involved in protecting ourselves and our families, friends, and neighbors from falling victim to illicit drug use. Ingenious chemists have used the Internet to research the chemical structure of existing psychoactive substances and use their skills to escape a strict reading of the controlled substances schedules. The result is to make extraordinarily difficult our long-standing strategy of relying primarily on an aggressive, supply-side, law enforcement–focused approach to reducing the availability of dangerous drugs. We can—and should—pursue each worthwhile option to combat this even though we know that we cannot immunize society against the pernicious effects of all NPSs, change hearts bent on evil, or save everyone who succumbs to drug abuse.

Key Takeaways

Novel Psychoactive Substances (NPSs) multiply the difficulties involved in protecting our-selves and our families, friends, and neighbors from illicit drug use.

NPSs like fentanyl and their illegitimate offspring like the nitazenes have brought an end to the era of drug experimentation.

We can—and should—pursue every worthwhile option to combat this scourge even though we know that we cannot save everyone who succumbs to drug abuse.



The United States and the international community regulate potentially dangerous drugs primarily through their controlled substances laws. The Controlled Substances Act of 1970 (CSA) created the basic federal regulatory system,REF which most states follow.REF Under the CSA, “hard” drugs like heroin that lack a legitimate medical use are altogether forbidden.REF Drugs that have a legitimate therapeutic use are subject to lesser degrees of regulation based on their potential for abuse and their safety when taken under medical supervision.REF International agreements to which the United States is a signatoryREF use the same basic scheme, which each nation separately enforces.REF

Historically, those drugs were derived from agricultural products. A classic example is the opium poppy, from which chemists can synthesize (for example) morphine. Another opioid—diacetylmorphine, or heroin—is a semi-synthetic drug because it is a derivative of morphine.REF Opioids are a matter of particular, long-standing concern because their promise of bliss, like the Siren’s call, entices a user down a path that leads to a short-term euphoria, but also to long-term addiction, misery, and death.REF

Agricultural products, however, are not the only drugs of concern. Nineteenth and 20th century advances in organic and analytical chemistry enabled scientists to isolate and manipulate the psychoactive ingredients in plants ordinarily used for religious or medicinal purposes to create what are known as Novel Psychoactive Substances (NPSs) or, colloquially speaking, “designer drugs.” Created in a laboratory from precursor chemicals, principally for recreational use, NPSs ordinarily are synthetically manufactured analogs of lawful or illegal drugs.REF NPSs can be just as enticing—and dangerous—as the ones derived entirely from their botanical ancestors.REF Sold in one or more formats—powder, pills, capsules, injectables, inhalants, vaping solutions, and so forth—they pose a variety of dangers.REF Fentanyl (an analgesic) is one of the best-known examples,REF but there are numerous others as well.REF

The problem of NPSs has existed for some time, but the number of such compounds has increased in this century.REF Over the past decade, they have assaulted America like the plagues that felled the Egyptians in the time of Moses.REF The only promised land is avoidance.

The term “novel” does not mean that the drug was recently created, only that it has recently become available (or noticed) in the illicit market.REF Some NPSs have existed for some time,REF and some even have legitimate uses but are also unlawfully created and sold.REF “[A] significant number of NPS were primarily developed for therapeutic purposes, but then started being misused and extensively abused for their euphoric effects, as legal alternatives to ‘traditional’ illicit psychoactive substances.”REF The number and types of NPSs available are large, and the task of regulating them has increasingly become an ongoing game of whack-a-mole.REF

A designer’s products might have a complicated structure, but his or her goal is quite simple: Create a new compound that mimics the psychoactive effects of a category of existing but illegal drugs that possesses a new chemical structure that is not clearly outlawed by federal or state controlled substances lawsREF or by international agreements to which the United States is a signatory.REF NPS are designed to attract users who have their own goals: obtaining a “legal high,”REF evading standard drug detection analyses,REF or pursuing “novelty” in drug experiences.REF A chemist’s goal is not necessarily to create a product that will endure forever or monopolize the NPS market even for a short period, but rather to make a quick buck by synthesizing a new compound that will attract “psychonauts” searching for “the ultimate high.”REF As explained below, however, a psychonaut’s novel experience can also be his last.REF

There is a growing literature discussing NPSs.REF This Special Report seeks to add to that corpus by educating readers about the principal NPSs of concern in America, summarizing the problems they cause, and suggesting what we can do about them.

The Most Troubling NPSs

Although we have known about NPSs since the 1980s, the problem hibernated until the first decade of the new century. Since then, however, it has exploded.REF More than 1,100 NPSs already exist, and additional ones are created every year. The number of potential synthetic opioids alone is in the thousands.REF A lengthy discussion of each one is beyond the scope of this Special Report, but five merit discussion as our greatest challenges today: fentanyl, synthetic psychedelics, nitazenes, synthetic cannabinoids, and cathinones. I discussed the first two in earlier studies in this series.REF The last three are summarized in the sections immediately below.

Nitazenes.REF Nitazenes (known by chemists as 2-Benzylbenzimidazole opioids) are a class of analgesic drugs. First synthesized back when Elvis Presley released “Heartbreak Hotel” in the 1950s,REF nitazenes were the product of an unsuccessful search for a more powerful but less addictive analgesic than morphine. The U.S. Food and Drug Administration (FDA), however, has never approved them as a human or veterinary medication.REF Dormant for 50-plus years, nitazenes emerged in the illicit drug market in 2019. Nitazenes can be sold as powders, liquids, pills, or capsules under that name, or they can be disguised as (or admixed with) other drugs.REF Some nitazenes are more than 10 times as potent as fentanyl, or 1,000 times more powerful than morphine.REF

As of mid-2022, the U.S. Drug Enforcement Administration (DEA) concluded that nitazenes are sold less often than fentanyl, but that practice could change over time given the nation’s focus on stopping illicit fentanyl’s spread.REF In fact, sales might already have increased without our knowledge, in part because medical examiners do not routinely test for NPSs.REF The drug Naloxone (Narcan) can reverse a nitazene overdose, but its potency might require multiple doses to be effective.REF Even then, it might not always be successful.REF

Synthetic Cannabinoids.REF In the 1970s, researchers created synthetic cannabinoids to understand the operation of the brain’s cannabinoid receptors, but their formula made its way into the hands of chemists who made synthetic cannabinoids available in the illicit market for recreational purposes.REF The term “synthetic cannabinoids” applies to all synthetic compounds that bind to and activate the cannabinoid receptors (CB1, found in the brain and spinal cord, and CB2, found in the spleen and digestive tract), as well as structurally analogous drugs.REF

Synthetic cannabinoids appeared in that market in this century, and their prevalence has increased steadily. More than 160 compounds have appeared since 2008 with new versions arising every two years.REF “These compounds clearly are the result of mining the literature on cannabimimetics.”REF Their psychoactive ingredient differs from the delta-9-tetrahydrocannabinol (THC) found in botanical cannabis, and the synthetic versions can have a far bigger “kick.” THC is only a partial agonist—that is, it does not fully activate receptors. By contrast, synthetic cannabinoids fully activate the brain’s CB1 receptors because they bind more readily with them than THC does, possibly by a factor of 100.REF Moreover, synthetics lack the buffering compound—cannabidiol, or CBD—that can moderate the euphoric and dysphoric effects of THC.REF For those reasons, the synthetic cannabinoids have “much more pronounced psychoactive effects.”REF

Marketed under the names Spice (the psychoactive ingredient of interest in Frank Herbert’s Dune series) or K2 (the world’s second highest mountain), synthetic cannabinoids are sold as powders, capsules, tablets, or plants sprayed with synthetic cannabinoids to look like old-fashioned “joints.” They attract users by offering a more powerful but street-legal alternative to the mild high that comes from inhaling THC.REF Used in low doses, “synthetic cannabinoids produce marijuana-like effects, including perceptual distortions and mood elevation.”REF But they can lead to more serious acute adverse effects than are seen with botanical cannabisREF—among them being an “increased heart rate, uncontrolled vomiting, acute kidney injury, panic attacks, hallucinations, psychosis, and seizures”REF—as well as a “30-fold” greater likelihood of needing emergency medical care.REF Synthetic cannabinoids can also be contaminated with toxins or other drugs like brodifacoum.REF Fatal overdoses from using synthetic cannabinoids have occurred (although they appear to be rare).REF

Cathinones.REF “In the beginning was the amphetamine.”REF Cathinones have a chemical structure similar to amphetamines and produce similar effects.REF Cathinones are marketed as “bath salts,” plant food, herbal blends incense, air freshener, insect repellant, or stain remover—as almost anything except drugs.REF But, like the sign advertising a “Free Lunch for $5,” that is “a marketing ploy,” because they “have no value” in bathing, cleaning, or any other advertised use.REF Like traditional amphetamines, low doses of cathinones can increase energy and elevate mood, but high doses can lead to “hallucinations, psychosis, increased heart rate, high blood pressure and hyperthermia, often accompanied by combative or violent behaviors,” as well as death.REF

The Nature of the NPS Problem

Health Risks. Over thousands of years, humans discovered that some plants contained substances that could be used for medicinal or religious purposes because of their therapeutic or psychoactive properties.REF White willow bark, for example, contains salicin, a chemical similar to acetylsalicylic acid, or aspirin, which has been used to treat inflammation or pain since the time of Hippocrates (400 B.C.).REF Once organic chemistry developed as a modern science in the 19th century, however, the possibility arose of creating therapeutic drugs in a laboratory from precursor chemicals instead of botanical products. That process accelerated with 20th century advances in chemistry, communications, and creativity.REF

Generally, those advances have benefited humanity. The 20th century synthesis of antibiotics, antivirals, and antineoplastics has saved millions of lives, while modern-day analgesics have reduced or eliminated the suffering that can accompany disease, injury, or surgery. Some discoveries, however, have created far more misery than they have alleviated, particularly when a new product is used for its recreational potential rather than its medicinal justifications. Just as a blade can be used as a surgical scalpel or a murder weapon, chemistry has been used to create some drugs that are far more dangerous than beneficial. NPSs belong to that category of drugs.

We have more to learn about NPS,REF but we already know that users face severe physiological and psychological health risks.REF Users can suffer from tachycardia, palpitations, chest pain, myocardial infarction, hyperthermia, hypertension (high blood pressure), seizures, immune thrombocytopenia (a low-level of platelets necessary for clotting), acute kidney injury, agitation, intracranial hemorrhage, strokes, panic attacks, neurocognitive deficits (e.g., memory loss and sleep disruption), paranoia, delirium, hallucinations, psychosis, and suicidal ideation.REF NPSs can also trigger unpredictable and violent outbursts.REF In the other direction, some new drugs—such as MPTPREF—cause permanent symptoms of Parkinson’s Disease by destroying dopamine-creating neurons, leaving users in an irreversibly frozen state,REF creating real-life images of the fictional depiction of Han Solo frozen in carbonite in The Empire Strikes Back.REF

And that’s not the worst that can happen (although that judgment is debatable). NPS use has also led to fatal overdoses,REF a problem that has recently grown.REF NPSs, such as fentanyl analogs (e.g., carfentanil, an elephant tranquilizer), are so potent that only a miniscule amount is necessary to render someone unconscious and shut off his autonomic respiratory process.REF Death can follow their use, or that of other NPSs, for any number of reasons. To start with, identifying the drugs consumed by someone who has overdosed can be a difficult undertaking. Some users do not know what they took (let alone its ingredients); they might have taken a combination of drugs (e.g., nitazenes mixed with heroin) that create peculiar or aggravated adverse reactions when consumed together;REF and emergency departments can find it difficult to identify it (or them)REF because NPSs are designed to evade standard recreational drug screening,REF and not every emergency department has the sophisticated laboratory equipmentREF that is needed to test for the full range of NPSs.REF Atop that, the body might quickly metabolize some NPSs, so if urine is used as the test matrix, it might be easier to identify the drug from a metabolite than from the drug itself (assuming that an emergency department knows the most common metabolite(s) of a newly introduced NPS).REF Even if the emergency department can identify the relevant NPSs, there might be no way to eliminate it forcibly from the patient and no known antidote.REF Even medical examiners, who do not act under the urgency of trying to save a life, might find it difficult to identify the specific cause of death.REF

Aggravating those problems are these facts: Chemists can churn out new NPSs faster than we can find, identify, and outlaw them, creating a “virtually endless supply.”REF It can take six to eight months to perform the necessary laboratory analyses to identify a particular generation of a new NPS, and later generations could have appeared during that time as replacements for the just-analyzed drugs.REF There is a possibility that NPSs can have unanticipated adverse effects that we will see only after their widespread, long-term use, which means that a large number of people might be harmed before emergency services, poison control centers,REF or laboratories identify the drug, devise a response, and communicate their findings across the medical communities in different states or continents.REF That delay might explain why there has been “an alarming spike” in the number of NPS-associated fatalities in some areas at different times.REF Even working assiduously to identify the cause of an increase in overdose fatalities, medical examiners cannot identify the precise number of NPS-related deaths. That is true because medical examiners do not test for every NPS in every drug overdose fatality, particularly if the medical examiner discovers fentanyl in a victim’s lab tests.REF The upshot is that even the dead might not be able to tell us why they died so that we can protect others.

Some drug policy scholars have argued that, despite the horrific damage that NPSs have inflicted on some individual users, they do not pose a major societal problem.REF The reason is that many NPSs do not initially attract a large audience, while most of the ones that do quickly lose their appeal because of the informal spread across the Internet of adverse information about their risks by the community of NPS users.REF “Few NPS achieve prominence beyond experimental use by psychonauts.”REF The overall, nationwide harm caused by those drugs, accordingly, has not been great. As a result, according to Peter Reuter and Bryce Pardo, the government might not need to schedule NPSs aggressively, perhaps because “the market self-regulates.”REF

That is a creative and intriguing suggestion. Ultimately, however, it is not a persuasive option for public policy implementation.

Reuter and Pardo are correct that we should focus our limited resources on the most dangerous drugs. The purposes of scheduling are to place out of bounds drugs that lack any legitimate medical use (which become listed on Schedule I) and to help law enforcement and regulatory agencies apportion their resources by identifying the relative risks of drugs that are both potentially useful and potentially dangerous (which are listed in Schedules II through V).REF Those are worthwhile goals. The problem is that the initial scheduling decision must be made quickly and often without time to decide exactly where in the CSA’s schedule of drugs a particular NPS best fits. Carolyn Coulson and Jonathan Caulkins do not see NPSs as a major societal problem, but they do acknowledge that initial classification decisions can be an all-or-nothing matter. The federal government can place a new, potentially dangerous drug into Schedules II–V only if there is an accepted medical use for it, and there may be no proof that it can be successfully used for treatment when it first emerges. If so, the only available slot is Schedule I, which prohibits a drug’s use for any purpose, medical or recreational.REF The solution to that timing problem, Coulson and Caulkins explain, is to create “a new ‘Schedule IA’ category for substances that should be prohibited from general recreational use, but for which absence of known medical applications is understood to mean ‘not yet fully explored’ rather than ‘considered and found wanting’.”REF

Even if that were a satisfactory legislative answer to this matter, it would require Congress to amend the CSA. Yes, the critics are right to say that we should make rational drug-policy choices. Yes, the current regulatory scheme might “overregulat[e] substances in ways that strangle potential medical research,” which no one wants to see.REF Keep in mind that illicit fentanyl is an NPS that has caused, according to the latest available federal figures, more than 70,000 overdose fatalities in one recent year.REF Only the most diehard libertarian would leave fentanyl regulation to market forces. Nitazene might not yet have the visible fangs that fentanyl has, but it is dangerous to presume that it won’t, and it certainly has at least the same venom. The number of people already killed through illicit fentanyl distribution, along with the number that might share that fate through increased trafficking in nitazenes, is sufficiently great to justify federal efforts to halt trafficking in both drugs. Consider also MPTP: It might not kill people, but the people whose brains it destroys, turning them into living statues, might wish that it had. And that does not take into account the as-yet-unknown worse NPSs that could pop up just around the corner.

Even if there were a good reason to assume that the market could do a better job than Congress, Congress has decided to prohibit trafficking in NPSs and other controlled substances by directing law enforcement agencies to use the criminal law to halt that conduct. Executive officials must respect that judgment until Congress changes its mind. Abandoning enforcement of the controlled substances laws in favor of market-based regulation is dereliction of duty. Congress has chosen a particular scheduling mechanism—a scheme that has only five schedules, not six—instead of leaving the matter to the discretion of executive agencies, and Congress expects law enforcement agencies to enforce the law. That is why Congress funds them.REF Also, the DEA cannot independently create a new Schedule IA because Congress did not grant the agency such law-making authority.REF

Congress’s judgment, by the way, was and is not an irrational or outdated one. Psychonauts might keep up to speed on the potential highs from NPSs, but the market cannot prevent the spread of those drugs to people who do not surf the Web for news about the adverse effects of NPSs, particularly the ones that are sold locally. They will wind up using drugs contaminated with fentanyl or MPTP. Ironically, even though the penal code is not ordinarily characterized as a “consumer protection” device, use of the criminal law can be a sensible strategy to protect the unwary or ill-informed.

To be sure, not every NPS poses the same risks as fentanyl or nitazene. Perhaps the CSA’s approach is overbroad in some instances, but it is not remotely irrational. Where to draw the line—distinguishing drugs that are appropriate for criminal prosecution from ones that are fit for only civil regulation or market control—is a classic matter of line-drawing, and Congress cannot be faulted for refusing to trust regulatory agencies or the “invisible hand” to deliver only “safe” illicit drugs. Besides, NPS traffickers can monitor the Internet for adverse reports on the compounds they distribute, as NPS users do, and in response can fool users by constantly varying the names of their products. It has happened before; in the 1980s, some sellers claimed that their fentanyl was actually heroin to avoid the stigma associated with the former.REF There is every reason to believe that it will happen again.REF Besides, it is up to Congress to decide just how paternalistic it wants to be regarding the use of the criminal law to regulate illegal drug use. Education might not dissuade some current and potential users from taking NPSs, because they have heard the false cry of past drug scare campaigns.REF (Does anyone remember the 1936 film Reefer Madness?) It is not irrational for Congress to decide that education and the criminal law work better than education alone.REF

Unsafe, Disuniform NPS Contents. Not everyone who synthesizes NPSs was educated at the California Institute of Technology and trained at the Sandia National Laboratories.REF Aside from making mistakes or being sloppy, they might be in over their heads when it comes to synthesizing NPSs that are both desirable and non-toxic. Underground laboratories also do not create NPSs in accordance with the “good manufacturing practices” that the FDA demands of modern-day public pharmaceutical companies.REF Secret manufacture of NPSs keeps the synthetization facilities and processes hidden from regulatory authorities, preventing them from inspecting the laboratory production process or reporting their existence to law enforcement authorities.REF Clandestine labs also lack quality control for their ingredients and products, and this allows impurities in, or dangerous combinations of, ingredients along with variances among the dosages in different batches of chemicals or within any one product such as a pill.REF Open retail sale of those products misleads the public into believing that they are safe, which can have unfortunate consequences.REF

There is limited data available on NPSs’ effects on humans and even less on their potential cross-toxicity with other legal or illicit drugs,REF combinations that might occur more often than we expect.REF The lack of safety testing leaves unknown valuable information about NPSs’ acute and chronic toxicity, including the difference between the maximum therapeutic dose and the minimum lethal one.REF Atop that, there is a serious risk of toxicity due to contamination—whether accidental, negligent, or deliberate—with other drugs. One especially pernicious additive is the veterinary medicine xylazine, which goes by the street name “tranq.”REF Tranq is added to fentanyl to extend the latter’s psychoactive effect,REF but it causes abscesses and putrefying, necrotic tissue in the limbs of humans, potentially leading to amputation or sepsis.REF The New England Journal of Medicine also has reported that some synthetic cannabinoids contain a derivative of the anti-clotting compound warfarin, which resulted in severe, long-lasting coagulopathy (a condition that impairs the ability to form blood clots, which can lead to excessive bleeding).REF Together, those factors pose a serious risk that toxic or hazardous compounds will wind up in NPSs and prove fatal to users.

NPSs put more than users at risk. Consider the risks to the chemists who synthesize NPSs. Twenty percent of the clandestine labs that law enforcement officers discover come to their attention as the result of a fire or explosion.REF As one DEA agent put it, industrial labs focus on “safety and quality control,” while clandestine labs focus on “secrecy,” which exacerbates the risky nature of the business.REF Keep in mind the risks that clandestine labs pose to the people who live in nearby areas, which include not only the release of toxic gases from the drug synthetization process,REF but also insidious long-term environmental harms and chronic illnesses from a devil-may-care disposal of the manufacturing process’s hazardous wastes.REF Finally, clandestine labs pose extreme risks to the law enforcement officers who enter to search the premises and arrest the cooks. One such officer put it this way: “I’ve never worked anything with the dangers of clandestine labs. As far as I’m concerned, this is the most dangerous thing in law enforcement a guy can do.”REF

Ongoing Dangers. The dangers of NPSs are unlikely to abate in the coming years. On the contrary, the versions of NPSs available today are not the end of the line as far as development goes.REF An increasingly large number of dangerous drugs can be synthesized in laboratories, and the people who succumb to “the lure of easy money” will not be put off by the risks noted above as long as they can continue to reap a steady stream of profits.REF

NPSs offer several attractions that botanically based drugs cannot offer. The latter burden growers with the need to find uninhabited locations that can be easily guarded over a months-long growing season and that possess ideal climates in politically stable regions with dozens of laborers available at harvest time. Even then, botanical drugs remain hostage to droughts, blight, and labor availability and costs. By contrast, NPS traffickers can hire professional chemists, who can use scientific reports available on the Internet (including the Dark Web) or in patent literature to synthesize NPSs quickly in makeshift or top-flight laboratories.REF As Jonathan Caulkins and Keith Humphreys have pointed out, the cost of ingredients or equipment is “trivial” when compared to a finished product’s selling price.REF “A modest investment in mixing equipment, a used pill-making machine, and a set of punch dies created to resemble the shapes and logos of popular drugs, are all one needs to become a do-it-yourself—albeit unlawful—pharmaceutical manufacturer.”REF It takes only “competent synthetics chemists” to synthesize NPS, so there is a sizeable pool of available “cooks.”REF There also is no growing field that must be guarded or any climate, weather, or insect problem that might ruin a harvest.

Other production, transportation, and distribution costs are far lower for illicit businesses than for legitimate companies. NPS labs have materially lower operating costs than those that legitimate pharmaceutical companies must bear because clandestine labs are free of those “pesky” safety standards that legitimate pharmaceuticals must follow as well as the environmental costs of proper waste disposal. There are no employment antidiscrimination laws for clandestine labs to follow, nor are there human resources offices with rules that must be accommodated. There likely are no thousands-of-miles-long supply chains, subject to interference at multiple points, that must be traversed in secret before the final products of those plants make their way to our nation.REF In short, illicit drug trafficking is unrestrained by any of the ordinary civil rules that every legitimate business must follow.

The Internet has changed the drug business by becoming “a primary base of operations for [NPSs], changing the dynamics of marketing, reducing risks to suppliers and buyers, and expanding markets globally without personal contacts.”REF The Dark Web makes it possible for sellers and buyers to transact business in relative secrecy without the need for a face-to-face meeting by using encrypted communications.REF Payment can be done anonymously via cryptocurrency that is difficult to trace, certainly for most state and local law enforcement departments, and a private express service can deliver NPSs to purchasers. Those factors give NPS dealers a financial leg up over old-style traffickers in heroin.REF

The Unknown Unknowns. One final problem must be noted: what we don’t know. At a macro level, we do not know the likelihood that NPSs will replace traditional, agriculturally based drugs. The emergence of NPSs over the past few decades, however, gives us reason to be concerned that the illicit drug business might have branched out into a new path that makes it increasingly more difficult to protect the public against improvident decisions.REF Or some of the same factors that increase the risk of the spread of NPSs—such as 21st century communications technologies and continued scientific advances—might help us to respond to this problem more effectively.REF Only time will tell.

At a micro level, we also do not know the risk—and accompanying fear—that NPSs might fundamentally change a user’s personality or create Frankenstein-like monsters out of what previously were ordinary people.REF Often present in (even if below the surface of) policy discussions about NPSs is the fear—something more than an anxiety but less than a terror—about a prospect that has not yet materialized but cannot be dismissed because it might exist just beyond the horizon: the odds that, in the search for new and not-yet-illegal compounds, chemists might synthesize drugs that entirely rejigger the human mind in a way that creates unmovably impassive or unstoppably violent personalities.REF We already know that some clandestinely synthesized products can freeze unwitting users into statues by destroying regions of their brains that are responsible for communicating with the rest of their bodies.REF What we don’t know is how many yet-to-be-created NPSs might have either that effect or the opposite one of generating a propensity for uncontrollable violence. Some chemists—the ones acting merely to make a profit—might create such compounds unwittingly. Others—the ones working for nations that wish us harm—might do so quite purposefully. Either motivation could potentiate this fear.

The prospect that unregulated science would create a Frankenstein-like creature has been troubling ever since Mary Shelly wrote a book by that name in 1818.REF The new science of genetic engineering makes that concern even more frightening.REF Variations of whether and how such a bastardization of biology, biochemistry, medicine, and morality could arise has been the theme of more than a few booksREF and filmsREF in popular culture. It is no exaggeration to say that NPSs pose a risk of permanent brain damage or transformation. An NPS might fundamentally and irreversibly change the brain, altering personality or mental health status on a life-long basis or creating zombie-like individuals that assume catatonic postures like some unfortunate souls on the streets of Philadelphia who mistakenly used MPTP-adulterated drugs.REF

Remember: The FDA’s mission is to protect the public against the potentially disastrous effects of new drugs like the incoming waves of NPSs. Congress created the FDA in 1938 to require an expert agency to review new drugs to be sure that they were safe before being publicly distributed.REF Prompted by the Thalidomide disaster in Europe in the 1950s, Congress augmented the FDA’s authority by passing the Drug Amendments of 1962, which vested the agency with the power and responsibility to refuse to approve any new drug until its sponsor has proved that it is not only safe, but also effective.REF The FDA review process has worked well to date, and no one seriously argues that it should be eliminated. The FDA, however, cannot protect the public against distribution of a drug it never reviewed. Distribution of NPSs—“products never tested or without established human use”—is tantamount to “experimenting ‘on the fly’ in human populations, with unpredictable results in popularity and toxicity.”REF That is precisely what the FDA exists to prevent, and for more than 85 years, the nation has endorsed that policy. The production and sale of NPSs flout that policy and endanger the public.

Potential Responses

Vigorous Intergovernmental Information Sharing. Knowledge might not be power, but it certainly is critical to sound public health decision-making.REF In her 2012 article “Designer Drugs: An Escalating Public Health Challenge,” Harvard Medical School Professor Bertha Madras proposed an excellent list of policy recommendations as to steps that we can take to address the challenges posed by NPSs.REF One of her recommendations is to coordinate the national and international information-gathering and monitoring activities of health-care professionals, academic researchers, and law enforcement agencies to identify emerging NPSs, their source chemists, and their effects by using automated web-crawler bots to lessen the diversion of human resources. Another recommendation was to collate, categorize, and place all information regarding the hazards of NPSs and the sources of their precursor chemicals on a website accessible by relevant national and international public health and law enforcement agencies.REF

To be sure, each nation’s domestic statutes regulate how its law enforcement agencies can pursue criminal investigations, and differences among the controlled substances and criminal laws effective in foreign nations committed to battling NPSs make it difficult to adopt a uniform transnational response to NPS trafficking. Nonetheless, some version of Professor Madras’s proposals has already been implemented to some extent and in some manner by the agencies involved in this battle, such as the U.S. Centers for Disease Control and Prevention (CDC), the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), the European Medicine Agency, and each nation’s national drug warning systems.REF Any of her recommendations that have not yet been adopted deserve serious consideration.

Aggressive Scheduling of NPSs. Domestic and international laws use a scheduling process to list drugs that cannot be marketed or prescribed at all versus the ones that may be distributed but only as prescribed by a physician.REF In the United States, federal law empowers the DEA to place an NPS into Schedule I on an expedited basis for a limited period.REF That provision is useful, but it helps only so much.

The multi-step, complex, detailed, date-driven review process that the FDA has used for decades to determine whether a drug is “safe,” “effective,” and “uniform” establishes a rigorous regimen to avoid mistakenly approving new pharmaceuticals that could damage the public.REF That process relies on a new drug’s sponsor—ordinarily, a large corporate pharmaceutical company—to provide the agency with a wealth of information about its composition and effect on humans. Chemists operating out of clandestine laboratories, working to synthesize new, barely legal drugs, do not supply the FDA with the information that legitimate pharmaceutical companies do.REF In fact, that would be the last thing that any of those chemists would even think of doing.REF

One result is that the clandestine manufacture and underground distribution of NPSs make the emergency scheduling process a rather helter-skelter affair. Mexican Drug Trafficking Organizations (DTOs) likely have far larger research and development budgets and staffs than the DEA has in its emergency scheduling department, which means that the DEA is always playing catch-up. Use of a particular NPS might become widespread and prove often to be fatal before the DEA, even with the FDA’s guidance, can acquire all of the relevant information needed to make an emergency scheduling decision.REF The steps involved in this process include spotting a new drug; identifying its chemical structure and characteristics; understanding its pharmacodynamics (effect on the body) and pharmacokinetics (movement through the body); learning whether there is a safe, quick-acting “off switch” like Naloxone; determining what is the best emergency treatment for someone under its influence; and disseminating that information and treatment recommendations to ER physicians, emergency service personnel, poison control center officials, and law enforcement officers.REF As a result, the cavalry might not arrive in time.REF

For effective emergency scheduling to work, therefore, it is critical that information about new NPSs be disseminated immediately, completely, and regularly among the world’s medical and public health agencies (e.g., the CDC, EMCDDA, and World Health Organization); established national medical organizations (e.g., the American and British Medical Associations); and the public health community (e.g., the American Public Health Association).REF Information sharing likely will not allow government officials and physicians to get ahead of clandestine NPS operations—they and the rest of us will always be playing defense against NPSs—but it might enable them to lag just a step or two behind.REF

One alternative is to place every new substance in Schedule I if it poses any potential risk to public health, regardless of its severity and despite the medical profession’s belief that it has legitimate therapeutic benefits.REF That approach, however, is not cost-free.REF First, it would deny physicians the ability to treat some seriously ill patients with the new drug.REF Second, that approach might make it difficult to alter an initial scheduling decision. There is an inherent, strong regulatory bias toward restrictively scheduling any new compound. Senior regulatory officials face little risk of congressional or public outrage from being unduly cautious, but they could face a career-ending public relations nightmare from allowing a drug to be distributed even under Schedules II–V if it causes severe injury to a nontrivial number of patients, especially to pregnant women or children.REF Finally, another harm from automatically placing every new NPS into Schedule I is that it might lead chemists to synthesize analogues that turn out to be more potent, and therefore more dangerous, than the parent drug—for example, acetylfentanyl and carfentanil are more potent than fentanyl—which would raise the stakes for each new round of whack-a-mole.REF

Aggressive Criminal Enforcement. Our traditional response to unlawful drug trafficking has been to use the criminal justice system aggressively as a regulatory tool. The fact of imprisonment quarantines whoever conducts that business while also increasing a drug’s street price.REF The threat of imprisonment hopefully deters others from choosing that path. Nonetheless, that strategy is unlikely to be successful for NPSs.

Legal hurdles make the prosecution of NPS traffickers riskier for the government than is the case with regard to heroin or cocaine. One hurdle is that the CSA requires the government to prove that a compound is “substantially similar to the chemical structure of a” highly dangerous controlled substance and has a “substantially similar” effect on the human nervous system.REF Ideally, the government would use a biochemist and physician to prove its case. Parties in the NPS business, however, have a powerful motivation to stay one step ahead of the law to become rich and remain free, so traffickers (particularly the Mexican DTOs) are able to hire expert chemists to generate products that fall just beyond the law’s reach.REF As a result, the government might not be able to prove its case against every defendant.

Congress cannot loosen the definition of a “controlled substance” too far or give the government the ability to redefine that term retroactively to cover materially different drug versions. The CSA requires proof that a party knew that (for example) a powder was a controlled substance (fentanyl, not talcum) in order to convict him of distributing a forbidden analogue (such as a new fentanyl variant).REF That might be difficult to prove in some cases, given the complexity of the compounds at issue. NPSs do not advertise themselves as unlawful, and the average person does not hold a PhD in chemistry. Consider that the Supreme Court of the United States has recognized that, while an average person might be able to identify a rifle, shotgun, or revolver as a “firearm,” he or she might not know that it is capable of automatic firing.REF So, too, the average person might know that a substance is a powder but not be aware that it is a controlled substance, let alone understand or even have ever heard the terms used to identify some NPSs, such as butonitazene.REF Compounds like those make the Federal Register read more like a graduate school organic chemistry textbook—with terms like “salts, isomers, optical isomers, and salts of optical isomers” of any listed chemical—than what we would expect to find in the penal code.REF Try asking an average person to understand those terms, and you can see why a prosecution might be dicey.

Organic chemists and the traffickers who employ them to produce NPSs doubtless know what those drugs are; no one could expect to make a living by selling legitimate “bath salts” for thousands of dollars for a one-ounce package. But those offenders are the most difficult ones to identify and prosecute. The government ordinarily begins an investigation by focusing on the retail dealers—the “little fish”—in the hope of persuading them to help the government step up the ladder to the “big fish” by an offer of charging or sentencing leniency. That might not be as easy in the case of NPSs as it is with regard to other illegal drugs. The criminal law requires that a criminal statute must be sufficiently clear to advise the average, reasonable person without a degree in biochemistry or law precisely what conduct is prohibited,REF and the average person lacks any knowledge of exactly how a particular compound is structured or what its effects will be.REF Together, those requirements might make more difficult the criminal prosecution of lower parties in the NPSs business whose testimony is necessary to prosecute their superiors, and without that testimony, the higher-level traffickers might skate. In sum, because of the difficulty involved in knowing whether a particular compound is an NPS, designer drug creators and suppliers are probably at a lesser risk than heroin traffickers of doing a long stretch in the hoosegow.

The bottom line is this: Several factors make impossible a complete reliance on an aggressive, supply-side, law enforcement–focused approach to halting or diminishing the availability of NPSs. That does not mean we should abandon law enforcement. To the contrary, we should continue to use it for what it does best: serve as a means of identifying and isolating the parties at every level of the process—from ingredient procurement to drug synthesis to NPS distribution and sales—who order or inflict violence as a means of doing business, as well as large-scale traffickers. That business injures or kills individuals and degrades their communities. The government should not breach its end of the social covenant by abandoning NPSs’ victims just because law enforcement alone will not make NPSs disappear everywhere, entirely, and eternally.

Aggressive Civil Enforcement. Some drug-policy scholars have suggested that, because NPSs are not marketed for medical-treatment purposes, governments might be able to use their civil laws governing alcohol, tobacco, ENDS (electronic nicotine delivery systems, or e-cigarettes), food, and consumer protection as NPS regulatory tools.REF The responsible agencies should seize the drugs involved and fine everyone, from financiers to chemists to large-scale or medium-scale traffickers to street-level dealers, to sanction every party in the chain of production and distribution.REF

The rationale for that approach is fourfold. First, that strategy invokes the “Precautionary Principle” that often guides decision-making in the environmental and consumer law fields: Potentially dangerous substances or actions should be prohibited or regulated unless and until their sponsor proves their safety under conditions of ordinary use.REF Second, civil enforcement is also “more agile” than criminal enforcement, the argument goes, because the constitutional demands on its exercise are fewer. Third, civil enforcement carries a lesser punishment than the controlled substances laws, thereby avoiding the societal costs of imprisonment. Fourth, civil enforcement avoids criminalizing possession rather than distribution. By focusing on the more culpable parties, civil enforcement might not provoke a public backlash.REF Here, that would leave the regulation of NPSs to the Commissioner of Food and Drugs (and his or her lieutenants) under the Federal Food, Drug, and Cosmetic Act and its implementing regulations.REF

That strategy would be a potentially useful one in some cases. Civil penalties have some deterrent effect, albeit not as much as the risk of imprisonment.REF But that difference might be important in this context. Because imprisonment is not a civil punishment, the civil law need not define unlawful conduct with the same rigorous precision that the criminal law demands. That explains why the “reasonable person” standard in tort law is not subject to challenge on the ground that the standard of care is unconstitutionally vague; forfeitures and fines are categorically less intrusive than imprisonment.REF Civil sanctions might be one effective way to respond to companies selling borderline-legal but nonetheless dangerous products in well-known national package store chains.REF A reason is that the notoriety of an FDA civil enforcement action could have such a damaging effect on a company’s reputation and stock price that it and others will steer far clear of selling any similar compound.

Nonetheless, the civil law ultimately has only a limited usefulness in this context. Civil seizures might be a straightforward way to remove questionable NPS products from chain stores, but that tactic might just move sales from package stores to the streets or indoors. Moreover, businesses operating clandestinely will not provide open and obvious targets for seizures, and laboratories operating in other nations would be beyond the reach of our civil laws. Insofar as civil fines are viewed by the players in the drug trafficking chain as just a cost of business, they would have no material effect on the supply of NPSs. Finally, law enforcement officers radiate a nimbus that no civil inspector can generate because the former can make arrests, while the latter can only issue citations. That weakens the deterrent effect that civil inspectors and enforcement agents would have on people in the NPS business.REF

Aggressive Border Protection. The smuggling of fentanyl from Mexico into the United States is not as immutable as the law of gravity. President Joe Biden could respond to it today by closing our Southwest Border with MexicoREF from whence most fentanyl enters this country.REF Yet he has proved unwilling to exercise that authority. So, even if Congress were to unite behind that policy (which won’t happen during this presidential election year) or the nation were to demand that we close our border (which might happen this November), that result will not occur soon.

Trying to close the border, however, is not likely to be a complete solution even for a President who is willing to use that authority. As a historical matter, we have not been able to shield the nation against the smuggling of drugs like heroin, all of which comes from elsewhere. Even if we built a solid wall along the entire 2,000-mile border with Mexico and reinforced it by laying a mile of claymore land mines immediately behind it, the most that we could hope for is to reduce the amount of NPSs smuggled into America over land. Why? Where there’s a will, there’s a way.

The potency of drugs like fentanyl or nitazene simplifies a smuggler’s job by multiplying his options. Since “a little dab’ll do ya,”REF a physical barrier would just prompt traffickers to switch to greater reliance on the U.S. Postal Service, private express mail companies, small planes, and drones to transport their merchandise into the United States.REF Of course, that does not mean we should make no effort to stem the DTOs’ reliance on NPS-carrying people to do their cross-border smuggling. On the contrary, we should make every effort. Increasing the costs of drug smuggling can lead to a reduction in demand and supply. More importantly, it can save lives. The Biden Administration’s matador-like wave-them-by approach to illegal immigration has doubtless killed numerous Americans from smuggled fentanyl. My point is that immigration and law enforcement alone cannot stop the death of thousands of people. We must pursue other approaches as well.

Enlisting International Cooperation. Should we seek assistance from foreign nations—particularly Mexico and China—to halt (or reduce) the quantities of NPSs produced in their homelands and smuggled into this nation? Perhaps, but enlisting their support to resolve what they see as America’s drug problem is problematic at best. The current president of Mexico, Andrés Manuel López Obrador (AMLO), is competing with President Biden for the role of Ignorer-in-Chief as far as drug smuggling is concerned.REF China certainly will not willingly help the United States to address this problem. Perhaps that is because China benefits militarily by addicting potential American servicemembers. Perhaps that is because China benefits financially by increasing the costs that illicit drugs inflict on our people. Perhaps that is because China sees our suffering as poetic justice for the Opium Wars that the West forced it to endure late in the 19th century. Or perhaps that is because schadenfreude is always a guilty pleasure, especially when it comes at the expense of an adversary. Whatever the explanation for its recalcitrance might be, China is not likely to assist the United States without receiving something in return so valuable that we would not find it in our interests to provide it.

Demand-Side Steps. With supply-side efforts and international assistance unlikely to halt NPS smuggling, we must also consider demand-side efforts. There are several options, though none is likely to be a home run.REF

We should pursue the search for an effective long-term “off switch” for NPSs similar to methadone and buprenorphine. That is particularly important in connection with the new opioid-like drugs such as nitazenes. “Given the widespread availability of fentanyl and increasing presence of ultrapotent synthetic opioids,”REF the failure to address this problem “[w]ithout innovative and effective treatments” could be quite devastating. “On the current trajectory, we can expect nearly a million deaths within the next decade.”REF That potential loss should prompt action.

No life-saving intervention, however, would be necessary for people who do not use NPSs. “The core of a prevention campaign is scientific evidence to document the potential consequences to users.”REF Education—of and by actual and potential users, public health officials, clinicians, medical examiners or coroners, laboratories, and legislators—is a critical life-saving tool.REF Education could reduce the number of new drug users, and it has been a successful strategy in connection with smoking and alcohol-impaired driving. Those education campaigns have saved thousands of lives.REF

Unfortunately, we have not witnessed the same effectiveness with our efforts to educate people against illicit drug use. In part, it has been difficult to persuade individuals to abandon their use of drugs or to dissuade potential new users from trying them. Hindering those efforts is the fact that, for the past 50-plus years, our culture has lauded drug use and lionized its champions. To change the mindset and conduct of the people at risk, we need to present truthful, factually accurate messagesREF with a strong visual component, particularly across social media, because the adolescent and young adult audiences we need to reach make great use of those platforms for news and play—as do NPS traffickers.REF The political branches should attempt to persuade social media companies to broadcast messages explaining the physical and psychological suffering that drugs like fentanyl mete out to their users.REF

Emphasizing an End to the Era of Drug Experimentation. One point that we do need to emphasize—everywhere and repeatedly—is that NPSs like fentanyl and their illegitimate offspring like the nitazenes have brought an end to the era of drug experimentation. Recreational drugs used in the 1960s, 1970s, and 1980s like marijuana could generate short-term and long-term harms but were not likely to produce immediate death, at least not on a widespread basis. Fentanyl can do so and has done so. “There is no safe amount of fentanyl, and unlike with heroin, no long-term users.”REF Fentanyl is sold as a stand-alone powder, as a secret ingredient in other illicit drugs, or sometimes in counterfeit pills.REF That fact is a particularly important one to bring to the attention of people in their 20s and 30s because they are the primary clientele for NPS traffickers.REF That generation might bewail the loss of their opportunity to pursue the same recreational drug experimentation as their fathers and grandfathers pursued. At the end of the day, however, Millennials and Generation Zers need to realize that more important than cursing the darkness is finding a light.


NPSs multiply the difficulties that our nation and others face in trying to protect ourselves and our families, friends, and neighbors from falling victim to illicit drug use. Ingenious chemists have used the Internet to research the chemical structure of existing psychoactive substances and use their skills to add new curlicues to those drugs in order to escape a strict reading of the controlled substances schedules. Because the criminal law must prospectively outlaw a substance in terms that the average person can understand, chemists and traffickers in NPSs have been able to stay one step ahead of law enforcement, perhaps even laughing at us as they do. The result is to make extraordinarily difficult our long-standing strategy of relying primarily on an aggressive, supply-side, law enforcement–focused approach to reducing the availability of dangerous drugs. It is feckless to believe that Mexico will assist the United States while AMLO is in power, and China is not likely to help us to combat our drug use without receiving a massive bribe in return—perhaps even abandonment of our current willingness to support Taiwan’s independence.

The remaining options are three.

  • At the wholesale level, pursue and punish major illicit drug traffickers to prevent individuals and communities from being victimized and to show respect for the lives and communities they have already ruined.
  • At the retail level, use law enforcement aggressively to reduce the violence associated with illicit drug trafficking by quarantining violent offenders.
  • At both levels, continue and augment demand-side strategies by improving our educational efforts and making voluntary and compulsory drug treatment more available.

These three steps are necessary to protect parties not yet victimized, to provide justice to the ones who have already suffered that fate, and to demonstrate that the government is serious about protecting the public from drug trafficking and its violence while extending help to those who made a wrong choice.

These strategies are also legitimate and worthwhile. We can—and should—pursue each one even though we know that we cannot immunize society against the pernicious effects of all NPSs, change hearts bent on evil, or save everyone who succumbs to drug abuse. We can make a serious effort to do so, however, and in the process, we will save some. Consider these words by Robert Browning:

Ah, but a man’s reach should exceed his grasp, Or what’s a heaven for?REF

That’s as good a game plan as any.

Paul J. Larkin is the John, Barbara, and Victoria Rumpel Senior Legal Research Fellow in the Edwin Meese III Center for Legal and Judicial Studies at The Heritage Foundation. I would like to thank GianCarlo Canaparo, Robert L. DuPont, Julia Jacobson, Bertha K. Madras, John G. Malcolm, Bill Poole, Lora Reis, and Nicole Robinson for valuable comments on an earlier iteration of this Special Report. Any errors are mine alone.


Paul Larkin
Paul Larkin

Rumpel Senior Legal Research Fellow