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Two

Humanity has long mined psychoactive chemicals from the natural world to worship gods, to feel bliss, to commune with the dead, to heal, to avoid problems, to escape ennui, to make art, or to just go on a little adventure of the mind. At first, people ingested these chemicals directly from living things, eating mushrooms, cactus buttons, and morning glory seeds; chewing coca and khat leaves; inhaling tree snuff; smoking cannabis, opium, or even the venom of toads; fermenting grapes and barley; curing tobacco; steeping leaves; and roasting beans.

Historically, only a few handfuls of different compounds have been used reliably to get people high, but over the past hundred years or so, humankind has learned to synthesize the active chemicals in laboratories and to manipulate chemical structures to invent new drugs—the numbers of which began growing exponentially in the 2010s. Anyone with computer acumen can acquire hundreds of psychoactive compounds that didn’t exist even a few years ago.

According to the European Monitoring Centre for Drugs and Drug Addiction, 150 new illicit drugs were bought and sold between 1997 and 2010. Another 150 appeared in just the next three years, and since then, in some years as many as 100 new chemicals have appeared, with synthetic cannabinoids especially common.

Though they can be incredibly potent and affect the body in new ways, these latest drugs aren’t conceived out of thin air. In fact, many are derived from the same naturally occurring chemicals our ancestors have been using for thousands of years. Fentanyl, for example, is a new plague, but its natural predecessor, the opium poppy, has been used (and abused) since at least the Mesopotamian era.

The story of fentanyl, however, can be traced to one man: Paul Janssen.

A Belgian chemist, Janssen was undoubtedly a genius. He could quote Homer in the Ancient Greek. During World War II he studied chemistry and other sciences at university in Namur, Belgium—­enrolling secretly, despite the Nazi occupation—and in 1948, when he was twenty-two, he funded a trip to America in part by beating opponents in chess, at venues including the Manhattan Chess Club. What Janssen was best known for was creating medicines. Over his lifetime, he was responsible for some eighty new medical drugs, including fentanyl. One biographer called him “the most prolific drug inventor of all time.” His brilliance wasn’t just in coming up with new medicines but in realizing that new medicines could be created in the first place.

Janssen was born in 1926 in the small Belgian town of Turnhout. When she was four, Janssen’s younger sister died of tubercular meningitis, a then untreatable condition that can now be controlled with antibiotics. Janssen was in high school at the time, and his sorrow over his sister’s death inspired his journey into medicine. He was mentored by his father, a family doctor in Turnhout, who would operate on patients in their own homes. In these first decades of the twentieth century, rather than give patients the available medicines—organ extracts and tonics that are nowadays discredited—Janssen’s father gave them placebos. “And he was absolutely right to do so,” Paul Janssen later wrote. “Naturally, there was insulin, cardiac glycosides, aspirin and morphine, but where most of the other medicines were concerned, one could safely say they did more harm than good.” Janssen’s father nonetheless started his own medicine company. After the discovery of penicillin, his company sold the antibiotic and also produced its own products, which mainly were combinations of existing drugs. The enterprise’s success did little to impress the younger Janssen, at the time a precocious chemistry and medical student.

“Come up with something better yourself, then,” his father challenged him.

At age twenty-six, Janssen began pursuing new chemicals, with some help from his father, who fronted him money and lab space. But Janssen wasn’t interested in slapping new labels on old chemicals. He wanted to create new drugs that actually made people feel ­better—and that he could patent. The key to this, he learned, was playing around with chemical structures. Based on the work of Nobel Prize–winning German medical scientist Paul Ehrlich, Janssen knew that adjusting the chemical makeup of a known drug, even just slightly, could create something that could affect the human body in dramatically new ways.

A year later, in 1953, Paul Janssen founded his company, Janssen Pharmaceutica, initially working out of the third floor of his father’s building. “We didn’t even have a calculator, let alone a computer for the simplest calculations,” Janssen wrote in 2000. “To reduce expenditure we economized by performing simple tests on pieces of gut from newly slaughtered rabbits, which I collected early in the morning from a butcher in Turnhout.”

Despite its modest beginnings, the company hit the ground running with its discovery of a drug called ambucetamide, used to alleviate menstrual pain. Janssen would also invent loperamide (Imodium), for diarrhea, as well as chemicals that became critical to the fields of psychiatry, mycology, and parasitology. To spur his company’s ascent, he recruited star Belgian scientists from the Belgian Congo, after the political upheaval there that would lead to the country’s independence and the end of colonial rule. He was soon managing a large staff—its members called him Dr. Paul—but still closely involved with creating new chemicals. He literally daydreamed about molecules. “I often watched him at meetings,” wrote Sir James Black, a physiology and medicine Nobel laureate of King’s College London, “when bored with the proceedings, finding solace inside his head as he doodled new chemical compounds!”

One of these new chemicals was fentanyl, which Janssen and his team first synthesized in 1959 by experimenting with the chemical structure of an analgesic called pethidine. He was hoping to find an alternative to morphine, the reigning pain reliever of its time.

Derived naturally from the resin of the opium poppy, morphine was chemically isolated at the dawn of the nineteenth century by German pharmacist Friedrich Sertürner, who named it for Morpheus, the Greek god of dreams. Janssen tested the effectiveness of fentanyl on lab mice, placing the mice on hot plates and slowly turning up the heat to gauge their reactions.

Fentanyl was particularly profitable for Janssen Pharmaceutica. Doctors found it superior to morphine because of the way it acted. Like morphine, it bound with a receptor in the brain (which we now call the “mu” receptor) to cause pain relief. But fentanyl came on faster, was much more powerful, and wasn’t as likely to cause nausea. “Fentanyl,” Janssen later wrote, “made it possible for the first time to perform lengthy operations and, together with its successors, heralded a revolution in the operating theatre. Without this compound and its analogue, sufentanil, open-heart surgery [as performed today] would not be possible.”

The drug was a revelation, and it went on to become the world’s most widely used anesthetic. Janssen Pharmaceutica was purchased by American behemoth Johnson & Johnson in 1961, and Paul Janssen continued working for the company, tasked with developing other types of fentanyl, referred to as analogues. But almost from the start, fentanyl’s potential addictive dangers were recognized, and it was placed under international control by a United Nations agreement in 1964. This led countries including the United States and the United Kingdom, in 1971, to schedule it—that is, to ban its recreational use. Indeed, its euphoric qualities would prove too much for many users to resist. “Fentanyl is a good medicine but a bad drug,” Justice Tettey, chief of the Laboratory and Scientific Section at the United Nations Office on Drugs and Crime, summed up later. “It has excellent pain relieving properties, but is liable to abuse and can rapidly lead to dependency.”

Despite fentanyl’s quick success as a painkiller in Europe, during the 1960s it was almost blocked for sale in the United States by the Food and Drug Administration. One vocal opponent to the drug’s approval was University of Pennsylvania anesthesiology professor Robert Dripps. A rare outlier who believed fentanyl’s high potency could lead to abuse, he eventually agreed to a compromise after being lobbied by Paul Janssen himself: fentanyl would be available, but only when diluted with another drug called droperidol, a sedative—also patented by Janssen—that was believed to mitigate fentanyl’s detrimental effects. A ratio of fifty parts droperidol to one part fentanyl produced a “bad high” when taken recreationally, Dripps and Janssen agreed, and thus was unlikely to be abused. The FDA approved this combination in 1968. Fentanyl’s success boosted Janssen’s bottom line, which drove Paul ­Janssen and his colleagues to develop many other fentanyl analogues. Some, like alpha-methylfentanyl, were never turned into medicines that were sold. Others, however, made it to market, including sufentanil, used in long-lasting surgeries, and carfentanil, a veterinary medicine that is the strongest fentanyl analogue ever made commercially.

At the very end of the 1970s, a pair of overdose deaths in Orange County, California, stumped authorities. A few bits of information were known about the victims. They seemed likely to have both used heroin, as shown by their telltale scarring (tracks) and the heroin paraphernalia discovered with their bodies. But toxicology reports bizarrely didn’t turn up any known drugs in their system. Soon, a half dozen more people in the county had died under similar circumstances, and then twice as many.

Around the same time, police began discovering a new drug on the street, China White. Traditionally, dealers of China White touted their product as the finest heroin available—pale in color and originating in East or Southeast Asia. “To get connected with China White is a sort of fantasy for [opiate] addicts,” Darryl Inaba, director of the Haight-Ashbury Free Clinic of San Francisco, said in a report in US Navy Medicine. This new China White had no heroin in it, however, and rather than a fantasy it was a nightmare. Instead of pure heroin from Asia, laboratory analysis determined that it contained something called alpha-methylfentanyl—a fentanyl analogue.

Though this particular chemical had been synthesized by Janssen Pharmaceutica, it was never developed into a medical product. The source of the China White remained a mystery. Presumably, the recipe had been stolen from scientific literature published by Janssen scientists, and then the drug had been cooked up by rogue chemists. But no China White lab was ever seized, and no one was arrested. There were plenty of guesses, however, including some wild speculation from a famed psychedelic chemist and drug expert named Alexander “Sasha” Shulgin. “Had China been developing some super-potent fentanyl analogues as potential warfare agents? Let the fantasy roll,” he wrote in 1997. “Maybe the Chinese were using second class citizens (the drug-using population of California) as guinea pigs for the initial human trials of their new drugs.” Also suspected were scientists in Russia, which had developed fentanyl problems of its own.

China White represented a fish-crawling-onto-land moment: it was the first popular, illicit drug synthesized by a rogue chemist that was new, rather than simply a copy of something already on the medical market. And thus, alpha-methylfentanyl was the first in a long line of new psychoactive substances that came to include K2, Spice, “bath salts,” and all the other substances this book is about. Back before they were called novel psychoactive substances, or NPS, they were known by another name: designer drugs.

Calling alpha-methylfentanyl China White was smart marketing, as it evoked a desirable type of heroin. What truly helped the product stand apart, however, was the fact that it was legal. Fentanyl itself had been illegal for recreational use since 1971, as a schedule II drug.** And chemically alpha-methylfentanyl was almost identical. But the key word is almost. It wasn’t identical. It had a unique molecular design. And therefore the police were powerless. “You could walk around with a shopping bag full of it and nobody could do anything to you,” observed Robert J. Roberton, chief of the state of California’s Division of Drug Programs.

Other fentanyl variations followed on alpha-methylfentanyl’s heels. In the early 1980s, more troubling reports about users injecting drugs that weren’t quite heroin emerged from California. In 1982 a man named George Carillo was brought to a San José hospital practically immobile, and his girlfriend, Juanita Lopez, came in a week later, also suffering from stiffness, paralysis, and other symptoms similar to Parkinson’s, except Carillo and Lopez were too young to have the disease. A handful of other victims with similar symptoms were soon identified. Eventually their condition was traced back to a new opioid they had injected called MPPP, which was intended to imitate heroin but had been synthesized incorrectly, inadvertently creating a different substance, MPTP, with disastrous side effects. This story at least has a silver lining, as research on the victims catalyzed new discoveries leading to advancement in Parkinson’s research.

It took the DEA six months to schedule a new drug, and by that time new analogues were already popular on the streets. So in 1984 Congress granted the DEA emergency scheduling powers, so the agency could ban drugs immediately. But even this was insufficient to stop the new fentanyl analogues, which sometimes started killing people before the DEA had even heard of them.

And so the US government began regulating drugs that didn’t yet exist. The Federal Analogue Act was signed into law by President Ronald Reagan in 1986. The legislation specifically went after fentanyls and what would become known as designer drugs and NPS. It made anything deemed “substantially similar” to schedule I or II psychoactive drugs—in either effect or structure—automatically illegal the moment it came into being.

However, banning something “substantially similar” proved challenging. Just because chemicals have similar structures doesn’t mean they will affect the human body the same way; in fact, quite often the effects can be dramatically different. Further, the law aimed at psychoactive substances, but what constitutes psychoactive can be debated. A strong cup of coffee can have a powerful impact, as can large amounts of chocolate and sugar.***

The US Federal Analogue Act is still used to prosecute makers of analogue drugs, yet little evidence exists that it has had a strong deterrent effect. In fact, since its enactment the number of new analogue drugs being consumed by Americans has skyrocketed. Most NPS are made in China, and since China lacks an analogue act of its own, drugs there usually must be banned one at a time, as they are discovered. (There are three United Nations international drug treaties—from 1961, 1971, and 1988, to which China, Russia, the United States, and most other world powers are signatories—and they also operate the same way, without an analogue act.) Thus, brand-new drugs that are automatically covered by US laws start off perfectly legal for manufacture and export in China, although in 2019 the country banned all fentanyl analogues.

The United States seems just as susceptible to new drugs as countries like Sweden, which lacks an analogue act. While Sweden has been devastated by dangerous analogues such as cyclopropylfentanyl, acrylfentanyl, and acetylfentanyl, the United States has been hit particularly hard by carfentanil, the veterinary tranquilizer that can be one hundred times more potent than fentanyl and five thousand times more potent than heroin. Carfentanil was responsible for killing more than eleven hundred Ohio residents between July 2016 and June 2017 alone.

At this point in the cat-and-mouse game between legislators and rogue chemists, warns Julijan “Sidney” Picej (an expert on new drugs who is from Ljubljana, Slovenia), the rogue chemists are so desperate for new products that they’ll try anything. “Good combinations are long gone. Their approach to finding a new flagship product is, ‘Anything goes, as long as it’s not fatal if you use it the first three times,’ ” he said. “It’s difficult for users and researchers to get any info, since the molecule was literally synthesized for the first time three weeks ago.”

In the mid-1980s, it wasn’t clear whether these types of “synthetic heroin” would become a plague or simply fade away. A University of California at Davis pharmacology professor named Gary Henderson studied the chemical impurities in China White and concluded that a single chemist was responsible for all of it. “Most likely he made a few grams of the drug—millions of doses—and then shut up his shop,” he told journalist Jack Shafer in 1985.

Henderson became the scientist doctors turned to when their overdose patients had strange blood samples, and the DEA consulted when it turned up inscrutable chemicals. He had already been researching fentanyl for years; his lab focused on how it was used to dope racehorses, whose urine turned up traces of it. He worked to develop a technique to identify fentanyl and began to understand the nature of the drug, including its potential for chemical manipulation. “Perhaps hundreds,” he said, when asked how many fentanyl analogues would be possible. “Maybe thousands.”

Henderson was way ahead of his time when it came to predicting the horrors not just of fentanyl but of NPS generally. “It seems we are still watching reruns of The French Connection while there is someone out there using a computer to search the chemical literature looking for new drugs to synthesize,” he told the US Senate’s Budget Committee in July 1985, a statement that was remarkably prescient. He coined the phrase designer drugs, defining them as “substances where the psychoactive properties of a drug are retained, but the molecular structure has been altered to avoid prosecution.” Often synthesized from common chemicals, they were skillfully marketed under attractive, exotic names, he added. His ١٩٨٨ paper “Designer Drugs: Past History and Future Prospects” is nothing less than prophecy, speculating accurately not just on the future of NPS chemistry but on the implications for law enforcement. “In the view of this author,” he wrote, “it is likely that the future drugs of abuse will be synthetics rather than plant products. A single gram of any very potent drug could be synthesized at one location, transported to distribution sites worldwide, and then formulated (cut) into many thousand, perhaps a million, doses. . . . Preventing the distribution of such small amounts of the pure drug will be exceedingly difficult. . . . In fact, any success we may have in curtailing the distribution of natural products such as opium, coca, and marijuana and preventing the diversion of pharmaceuticals will only stimulate the development of potent synthetic substitutes.”

*** Schedule I drugs have “no currently accepted medical use and a high potential for abuse,” while Schedule II drugs have “a high potential for abuse, with use potentially leading to severe psychological or physical dependence,” according to the DEA.

**** The United Kingdom went even further with an analogue act thirty years later, in 2016, when it enacted the Psychoactive Substances Act, which sought to ban anything that could get a person high, with medicine, alcohol, cigarettes, and caffeine specifically exempted. The purpose of the bill was to combat “legal highs,” such as synthetic cannabinoids and ecstasy knockoffs, which had been sold lawfully in head shops—but the bill had unseen ramifications. The Church of England and the Catholic Church were worried that using incense in services could lead to prosecution, and the bill’s implementation was delayed over concerns that the difficulty of defining psychoactive might make the law problematic to enforce. Ultimately it was implemented and did successfully remove “legal highs” from store shelves, but the long-term ramifications aren’t yet fully understood.