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Fighting the Uphill War Against Illicit Drugs and Overdose Deaths: Detecting Emerging Designer Drugs and Opioid Analogs

Early warning system helps lessen the harm from the tsunami of illicit drugs flowing into the U.S.
Date Published
September 18, 2023

Toxicologist Barry Logan parked his rented RV just outside the gates of the Ultra Music Festival in Miami. It was a sunny, March day in 2014, and he was there to do some science.

He and his team randomly stopped attendees — who were on their way to see Diplo, Tiesto, Loco Dice, and other electronic dance music stars — and asked them if they would pee into a cup, open their mouth for a saliva swab, and give a little blood.

Logan and his research team wanted to know what drugs the music fans were using, and 145 of them agreed to participate, tempted by either their love of science or the $20 Dunkin’ Donuts gift card Logan offered in return. Most said they were only using marijuana or cocaine, but 33 said they had also taken “Molly,” “Ecstasy,” or some other synthetic drug.

Despite the insistence by most of the participants that they knew what drugs they were on, Logan’s analysis found an array of drugs that often didn’t match what people believed they had ingested. The research, supported by a National Institute of Justice (NIJ) grant, was so revealing that Logan drove his RV to additional festivals to conduct more research in 2015 and 2016. The results were the same: The drugs were varied and often not what people thought they had taken.

Logan says that the Miami experiment planted the seed for a more extensive national program to analyze and rapidly identify recreational drugs as they appear across the United States. That NIJ-supported program, NPS (which stands for novel psychoactive substances) Discovery, is run by the Center for Forensic Science Research and Education (CFSRE) and is based in Willow Grove, Pennsylvania. NPS Discovery serves as a drug early warning system for public health officials, emergency room physicians, crime labs, law enforcement agencies, and others. Logan is the executive director of CFSRE.

The nature of the drugs that now flood streets across the country emphasizes the importance of the network. The drugs are no longer predominately the “party” drugs that Logan encountered in his RV lab, although those drugs are still plentiful in evolved forms. The drugs of greater concern now are those with higher risks of killing people: fentanyl, fentanyl analogs, and nitazene analogs.

NPS Discovery screens all the drug samples sent to the program for identification and toxicity. While they examine a wide range of drugs, including the new wave of designer drugs, Logan’s work focuses on the opioids laced with the fentanyl and nitazene analogs. The numbers from the Centers for Disease Control and Prevention (CDC) show why.

According to the CDC, an estimated 107,622 drug overdose deaths occurred in the U.S. in 2021, an increase of nearly 15% from the 93,655 deaths estimated in 2020. Of the 2021 deaths, almost 81,000 were attributable to opioids, primarily fentanyl. The CDC notes that deaths from “psychostimulants,” such as Ecstasy and cocaine, also increased in 2021 compared to 2020.

The work Logan conducted from his RV in Miami came as the national wave of opioid use was gaining strength and serves as a marker in the evolution of illicit drug use in the U.S. “The drugs we were identifying back then were the stimulants, the party drugs, the rape drugs, drugs that have similar properties to ecstasy,” Logan said.

Those drugs were changing every year, in part to keep ahead of being “scheduled” — or made illegal — by the Drug Enforcement Administration (DEA). As the illicit drug trade evolved, experts at CFSRE, supported in part with NIJ grants, analyzed samples of drugs seized at the southern border, drugs from the streets, and drugs found with people who had overdosed and died.

Since its creation in 2015, NPS Discovery has become steadily more sophisticated and can pull in data from a host of channels that weren’t available early on. Logan says, “We have far more collaborators, including internationally. They rely on our information, and we rely on theirs.”

Alex Krotulski, a CFSRE associate director and program manager for NPS Discovery, has seen the growth of the illicit and increasingly toxic drug trade in the U.S. With the opioid crisis came a whole new class of drugs and drug users, along with a dramatic increase in overdose deaths. The federal efforts to dampen abuse by limiting legal prescriptions of opioids had the unfortunate effect of creating greater demand and wider use of illicit fentanyl and other opioid analogs.

Fentanyl, a synthetic opioid about 30 times more potent than heroin, was developed as an analgesic, or painkiller, for surgery. Because of its potency, fentanyl quickly gained notoriety among drug users and first appeared in street drugs in the late 1970s. The demand was high, and Logan recounts how some people with substance use disorders would go through medical waste looking for fentanyl pain patches, which were primarily used on cancer patients. “They would chew them,” he said.

After fentanyl appeared in the late 1970s as an additive to heroin, illicit drug distributors realized it was much easier to make and distribute than heroin. “Fentanyl is certainly easier to make [than heroin] because you don’t have the whole supply chain of growing poppies in Asia, then processing them into heroin in jungle labs,” Logan said. “And then, because heroin is a lot less potent than fentanyl, there’s a lot more bulk to move around.”

Logan explains that from a drug smuggler’s perspective, the fact that fentanyl is 30 to 40 times as potent as heroin means that, “in terms of moving it across the border, fentanyl is a much easier drug for the cartels to move around.”

Over the past decade, the illicit drug trade primarily developed and used fentanyl analogs. By altering a few atoms in fentanyl, drug labs — many in China — could create analogs such as alfentanil and carfentanil that were more powerful than fentanyl and legal. Some of the analogs were new and others, like carfentanil, already existed. Carfentanil was developed in 1974 to allow veterinarians to sedate elephants and rhinoceroses.

When a new analog appeared on the streets, the DEA would list it as illegal, and the illicit labs would respond by creating a new, legal analog. This deadly game of “Whack-A-Mole,” as Logan and Krotulski describe it, continued until 2018 when the DEA listed all drugs related to fentanyl as illegal — a move referred to as class-wide scheduling.

In 2020, China responded to the DEA action by also restricting the manufacture of fentanyl and its analogs, and the flow into illicit drug networks slowed and shifted to Mexico and, to a lesser extent, India. Although suppressing fentanyl and its analogs lessened one stream of the illicit drug trade, it spurred a new one. “As a direct result of the DEA scheduling fentanyl analogs,” Krotulski said, “we saw a new class of opioids fill that void.”

That new class is from the 2-benzyl benzimidazole family, and the analogs are referred to as nitazene analogs (or just nitazenes for short). “Over the last four or so years, we’ve seen a variety of these analogs, just like how we saw the growth and diversity of fentanyl analogs,” Krotulski said. And similar to fentanyl analogs, “the nitazene class has several different drugs associated with it, so everyone should use the term nitazene analogs rather than just nitazenes,” he said.

 “Nitazene itself is not a drug, but rather a class of drugs. We are in this period where we’re repeating that [fentanyl] history,” Krotulski said. “We’re just replacing the fentanyl analogs with nitazene analogs.”

Like the early days of fentanyl and fentanyl analog use, the DEA has not yet listed nitazenes as an illegal class of drugs. The agency has issued public warnings about individual nitazene analogs when they have appeared in specific regions. In June 2022, for example, the DEA’s Washington division issued a warning to the District of Columbia and the surrounding states that isotonitazene, or ISO, was being sold in the region.

Nitazenes, according to a DEA information sheet, “are being sourced from China and being mixed into other drugs.” Isotonitazene was first identified in 2019 in the Midwest, then in Southern states and the Eastern seaboard. “Currently, nitazene [analog] reports are still relatively low, especially compared to fentanyl,” the DEA stated, but noted that “this emerging drug [class] is something to keep an eye on.”

That is exactly what Logan and Krotulski are doing through their NPS Discovery program, which has received more than $2.5 million in NIJ grant support. The regional progression of isotonitazene is a familiar pattern in drug distribution. “What’s happening in the Northeast can be very different from what’s happening in the South, or on the West Coast,” Krotulski said. “You see localized outbreaks, depending on how the drugs are being distributed.”

What causes an outbreak and overdose cases, including deaths, in one region but not another depends on the potency of the specific, distributed analog. “With fentanyl analogs, you had a range of potency,” Krotulski said. “You had drugs that were less potent than fentanyl, and more potent. Carfentanil is reported to be 100 times more potent than fentanyl. So, you had a range of potencies, and it’s the same with nitazene analogs. Some nitazene analogs are less potent than fentanyl, while some are considerably more potent.”

Currently, fentanyl and fluorofentanyl are primarily made in Mexico, while the new nitazene analogs are “mostly being made in China, in very high-end labs,” Krotulski said. “The chemists know very much what they are doing and, from what we’ve heard, that is happening in industrial cities like Wuhan. What they’re doing technically is not illegal in China, or the United States for that matter. But they know what they are making, and the drugs are quite pure before they get here.”

People in China and Mexico are not the ones selling the drugs on the streets of Atlanta or Philadelphia, Krotulski said. “You’ve got a whole bunch of different hands the drugs are passing though, and sometimes you’ve got people who are trying to make their mark on their own product. That is why we see different products that end up with different colors. They want people to know that the purple ‘heroin’ is their ‘heroin.’ There are a lot of layers, and trying to gather the confirmatory data is really difficult to do.”

Isotonitazene emerged around Chicago in 2019, then another analog, metonitazene, appeared in Tennessee. “There is some level of distinction based on the manufacturers, or dealers, or gangs, that is associated with these regionalized areas. I don’t how many people that is. It could be one person, or it could be a hundred people, depending on where and at what level the drug is coming into a region,” Krotulski said.

To identify isotonitazene in Chicago, metonitazene in Tennessee, or a fentanyl analog in Seattle, CFSRE’s NPS Discovery obtains samples and tries to identify them in as little as a few days. Once they identify a drug, the program’s scientists alert other forensic scientists, hospitals, first responders, and law enforcement officials in the affected region.

The NPS Discovery drug database contains more than 1,100 drugs. When a sample comes in to the CFSRE, be it from a medical examiner’s office, a law enforcement agency, a crime lab, or even an emergency room or concerned doctor, their scientists begin the process of determining what drugs are in the sample.

“We get powders, pills, plant materials, [and] syringes, and we search for specific drugs in those samples,” Krotulski said. “We also get a lot of toxicology samples, whether it be blood, urine, serum, or plasma. When the samples come in the door, we first take them through a non-targeted screen using our comprehensive mass spectrometry library.”

Once the scientists know which of those 1,100 database drugs might be present, the sample is triaged through several secondary (or confirmation) tests, depending on the nature of the sample and what drugs are indicated.

“If it’s a blood sample, we’ll have to decide if we want to quantify the amount of drugs present, or [if] we just want to report the result qualitatively,” Krotulski said. “If it’s a urine sample, we may need to figure out if we are looking for the drug or its metabolites [the substances made when the body breaks down the original drug]. Or conversely, if we find a metabolite, then we have to figure out what the parent drug ingested was.”

Beyond the direct testing of the samples, the NPS Discovery experts also do “sample-mining,” which helps them try to predict what drugs may emerge. “We’re trying to be, as other people have called it, prophetic — or predictive of the future,” Krotulski said.

Of the 1,100 drugs in the program’s database, only 300 to 400 exist in analyzed samples. “We’ve got a lot of drugs in the database, and that gives us the opportunity to identify [new street drugs] if they emerge,” Krotulski said. “Some things we know we may never see, but some are drugs that we think we’ll see tomorrow or in the near future and want to be as prepared as possible.”

The drugs flowing into the U.S. are changing more in their mix than in their amount, according to CFSRE’s NPS Discovery experts. “The nitazene analogs have replaced the fentanyl analogs,” Krotulski said, “but they are not replacing fentanyl itself. There is no indication that anything is replacing the amount of fentanyl across the country right now.”

Despite the restrictions on the fentanyl analogs, the continuing presence of fentanyl itself, combined with the emergence of nitazene analogs, means the overall state of illicit drug use in the U.S. “is definitely moving in a worse direction,” Krotulski said.

NPS Discovery hopes to strengthen its collaborations with the DEA to share emerging drug data. “We have data on the health impacts and the deaths associated with these new drugs and that is reflected in the DEA files,” Logan said. “We’re optimistic that there will be more opportunities for collaboration.”

Illicit drug use in the U.S. has a long history and continues to evolve. “If you think you know what is going on based on data from three months ago, you probably don’t know much at all,” he said. “It’s very dynamic and it’s not ending. Certain things are changing, but overall, the concept of newly emerging drugs infiltrating the drug supply is continuous.”

Logan noted that some evidence shows that drug deaths are flattening off, particularly with respect to fentanyl. “But with somebody inventing a new way of making fentanyl, a new way of getting it into the country, or an easier way to distribute it, that could change overnight. And overall, there is no evidence of a decline in drug use or drug availability,” he said.

NPS Discovery’s realistic goal is to lessen the harm.

Date Published: September 18, 2023