Underground labs in China are devising potent new opiates faster than authorities can respond

CINCINNATI, OHIO—Miller Atkinson was an addict from the very first time he shot up with heroin. "I fell in love with it. Everything else fell to the wayside," says the 24-year-old. "There was nothing that could have stopped me from getting high."

And that's what he did every day, for 9 months, in his family's upper middle class neighborhood in this Midwestern city. He dropped out of the University of Cincinnati. Like other users, he built up a tolerance to heroin and needed larger doses to find euphoria. Then, about 4 years ago, a powerful new combination hit the streets here: heroin cut with fentanyl, a synthetic opiate about 100 times more potent than morphine that's used to alleviate pain during and after surgery and in late-stage cancers. "It started trickling in, and we were like, ‘Wow, that was good, we need to get more of that,’" he says. "It was more intense." So much so that friends who shot up with fentanyl-laced heroin started dying.

Atkinson was one of the lucky ones. After several misdemeanors and a felony heroin possession charge, he got his life back on track, and he is now studying for the law school entrance exam.

Fentanyl and its analogs are new faces of a worsening scourge. The United States consumes 85% of all the world's natural and synthetic opiates, which in 2015 factored in 33,091 U.S. deaths, up more than 4000 from the previous year, according to the U.S. Centers for Disease Control and Prevention. Opioid overdoses have quadrupled since 1999. When average U.S. life expectancies for men and women edged downward last year, for the first time in decades, many health professionals blamed opiate abuse.

The opium poppy is no longer the starting point for many of the opiates on the street. The new compounds, often sold mixed with heroin, originate in illicit labs in China. "For the cartels, why wait for a field of poppies to grow and harvest if you can get your hands on the precursor chemicals and cook a batch of fentanyl in a lab?" says Tim Reagan, resident agent in charge of the U.S. Drug Enforcement Administration's (DEA's) Cincinnati office.

DEA classified fentanyl as a schedule II drug decades ago, which makes it a felony to sell or use the opiate without a prescription. But in China, until recently, fentanyl was largely unregulated. In late 2015, the drug agency persuaded its Chinese counterpart to add 116 synthetic drugs to its list of controlled substances; fentanyl and several analogs were included. In response, underground Chinese labs began tweaking the fentanyl molecule, which is easy to alter for anyone with basic knowledge of chemistry and lab tools. By adding chemical groups, unscrupulous chemists have created new, unregulated variants, some of them even more potent than the original.

Public awareness of the crisis spiked last spring, after music icon Prince's death from an overdose of fentanyl. But in the months since then, the chemical one-upmanship has deepened the opiate crisis, as new and nastier substances appear on the streets in places like Cincinnati. The fentanyl derivatives not only allow makers and dealers to elude law enforcement; they blindside public health authorities and make addiction even riskier. "It's just going to get worse," Reagan says.

Last July, police and scientists here were bracing for a new villain—perhaps the deadliest fentanyl cousin yet. "We were hearing about something so dastardly we had to be prepared," recalls Lakshmi Sammarco, the coroner for Hamilton County, which includes Cincinnati. Carfentanil, an elephant tranquilizer that apparently had never been studied in humans, was showing up mixed into heroin in nearby cities and felling addicts. That month, a Canadian man was arrested in Calgary after authorities intercepted a 1-kilogram package of carfentanil labeled as "printer accessories," which he had ordered from China. Other synthetic opiates had found their way into Ohio via Canada, so it was only a matter of time before carfentanil would make the journey as well. "We all looked at each other and said, ‘Alright, buckle your seat belts, this is going to get very bumpy,’" Sammarco says.

Fentanyl crosses the blood-brain barrier with ease. It binds to opioid receptors and floods the brain with dopamine, which creates intense euphoria but also slows the heart and depresses breathing. For most individuals, a lethal fentanyl dose is about 2 milligrams—an amount so minuscule that in a test tube it looks like a few grains of salt clinging to the glass. Carfentanil is 100 times stronger, making it about 10,000 times more potent than morphine. Crime labs keep autoinjectors of naloxone, the lifesaving opioid receptor antagonist, within reach in case their personnel are accidentally exposed to synthetic opiates.

Realizing what they were facing, Sammarco and her colleagues shifted into crisis mode, warning first responders that carfentanil overdoses could require double or triple doses of naloxone. They cautioned users not to dose up alone, and banned cops and emergency crews from testing drugs at crime scenes. (Last September, 11 police in Connecticut fell ill after accidentally inhaling fentanyl that was kicked up into the air during a drug bust.)

Then, the bomb went off. Over 6 days in late August 2016, Hamilton County saw 176 drug overdoses, primarily from carfentanil, the coroner's office says. After the initial shock wave, use of the drug ebbed—it was simply too powerful and dangerous for addicts and dealers looking to make a quick profit. "We get a little bit of breathing room," Sammarco says. "But we're always waiting for the other shoe to drop."

Hoping to stem the tide of synthetic opiates, DEA has taken the fight to China, as prolific a maker of illicit drugs as it is of legitimate chemicals. According to a U.S.-China Economic and Security Review Commission report last month, "China is a global source of illicit fentanyl and other [new psychoactive substances] because the country's vast chemical and pharmaceutical industries are weakly regulated and poorly monitored." In response to U.S. pressure, China has scheduled fentanyl and several other derivatives.

Opiates 2.0 By adding chemical groups, illicit chemists in China have created new analogs of fentanyl, some of them even more potent than the original. Many are sold openly to U.S. buyers as "research chemicals." Weaker variations Acetyfentanyl C 21 H 26 N 2 O

H N O Butyl-fentanyl C 23 H 30 N 2 O

H N O Furanylfentanyl C 24 H 26 N 2 O 2 Stronger variations 3-methylfentanyl C 23 H 30 N 2 O

H N O Carfentanil C 24 H 30 N 2 3

H N 3 Furanylfentanyl C 23 H 30 N 2 O 2 V. Altounian/ Science

But enforcement is tough. Chinese labs producing the synthetic opiates play hide-and-seek with authorities. On their websites, they list fake addresses in derelict shopping centers or shuttered factories, and use third-party sales agents to conduct transactions that are hard to trace. The drugs themselves are easy to find with a Google search and to buy with a few mouse clicks. A recent check found more than a dozen Chinese sites advertising fentanyl, carfentanil, and other derivatives, often labeled as "research chemicals," for sale through direct mail shipments to the United States. On one website, carfentanil goes for $361 for 50 grams: tens of thousands of lethal doses.

The cat-and-mouse game extends to chemistry, as the makers tinker with fentanyl itself. Minor modifications like adding an oxygen atom or shifting a methyl group can be enough to create whole new entities that are no longer on the list of sanctioned compounds. Carfentanil itself was, until recently, unregulated in China.

The coroner's office in Cincinnati overflows with work. Lab analysts have set up shop in makeshift office spaces in the hallway. They are coping with a months-long case backlog created by the waves of new opiates washing into the region. In Hamilton County, as in many other jurisdictions, drug dealers can be charged with manslaughter when a customer overdoses and dies, but prosecutors can't charge a dealer without verifying what he sold. To confirm that victims have overdosed on illegal opiates and to support prosecution of drug dealers, Sammarco's team must parse the chemical composition of seized samples.

Other users can't help, as they generally "don't know what they're taking," says Tom Fallon, a lead investigator with the Hamilton County Heroin Task Force. A computer readout of one sample in the crime lab here illustrates why. The batch includes heroin, of course, but also caffeine, an antihistamine, an unidentified fentanyl compound, carfentanil, and another nasty analog, furanylfentanyl. Some recently seized batches have also been laced with ketamine, an anesthetic that has gained popularity in China as a recreational drug.

When the carfentanil wave struck, the county lab scrambled to prepare its analytical tools. One challenge was simply finding samples to compare to seized material. Veterinarians no longer use the substance, and commercial labs don't stock it. Eventually the coroner's office procured an expired batch from a nearby zoo. By October 2016, the county toxicology lab had fine-tuned its testing of blood and urine samples using a gas chromatograph mass spectrometer, which can find carfentanil at its smallest detectable dose. The machine shears mystery molecules into fragments, weighs them, and compares the pattern of masses to those from a known molecule. Like splitting Lego creations, breaking up the molecules produces the same pattern each time.

Another challenge with carfentanil is the dearth of literature on how much would cause a human to overdose or die, explains Bob Topmiller, Hamilton County's toxicologist. First responders and crime lab chemists are now building a body of research on its effects. "We're not a research lab," he says, "but there's a lot of information we've been able to obtain over the last several months that we've been able to share with other labs," such as molecular structures and toxicology reports.

Like other regions around the United States coping with a tide of mystery opiates, Hamilton County gets help identifying the compounds from DEA's own facilities, including the Special Testing and Research Laboratory, a plain building in an industrial development in Sterling, Virginia. In contrast to the Hamilton County coroner's office, the Sterling lab is brightly lit and uncluttered. Director Jeffrey Comparin and his team have at their disposal an arsenal of detection and chemical dissection tools for identifying unknown drugs. "It's not uncommon for us to build up a molecular model from scratch as we go," he says. A DEA chemist demonstrates by snapping a methyl group onto a plastic model of fentanyl.

China eventually banned methylfentanyl, driving down its production and pushing it deeper underground. Its crackdown on fentanyl and several analogs in 2015 led to a marked decline in those synthetic opiates in the United States, DEA says. And last month, after extensive negotiations with DEA, China added carfentanil and three more fentanyl analogs to its list of controlled substances.

Even before China scheduled carfentanil, the scourge had begun to fade in Ohio. Sammarco expects the final toll from that analog in Hamilton County last year, after all analyses are completed, will top 70 deaths. But a new threat has appeared. Traces of an unidentified fentanyl analog have cropped up in several batches from crime scenes. Hamilton County's scientists will search for a molecular match, add it to the list—and hope the new wave is less deadly than the last.