Underground labs invent new fentanyls faster than forensic labs can keep up
Illicit laboratories do a good criminal job synthesizing new forms of dangerous drugs that go unnoticed, but a new method could detect variants of the powerful opioid fentanyl before they are even cataloged by authorities.
Measuring the characteristics of a suspected pill and comparing them to computer-generated reference values could reveal chemical signatures of previously unseen fentanyl variantsthe researchers report April 27 on bioRxiv.org. Although the system is not yet ready for use by law enforcement, the ability to look beyond the molecules on official books could one day help them stay ahead of opioid traffickers.
Used in anesthesia and analgesic, fentanyl is up to 100 times more powerful than its cousin morphine. Just two milligrams… the amount that fits on the tip of a pencil — is potentially fatal, and the United States has reported more than 72,000 overdose deaths in 2023 alone. Fentanyl contains no natural ingredients and no underground labs can modify its structure just enough to avoid detection while still retaining its heroic effect. This has made it cost-effective to add a powerful substance to pills that many users don’t know they’re taking.
The only way experts can tell if a pill contains a variant of fentanyl is to compare it to a reference library created by analyzing pure chemical compounds in the lab. But the math says there are billions of possible forms of fentanyl — and experts only know about 60,000. Forensic and toxicology labs can’t keep up. “It’s become a real mole problem,” says biochemist David Wishart of the University of Alberta in Edmonton, Canada, who was not involved in the work.
Bioanalytical chemist Tom Metz says: “Pure forms won’t get us where we need to be. » Metz, of the Pacific Northwest National Laboratory in Richland, Wash., and his colleagues set out to eliminate the need for traditional reference libraries. In previous work, they used two customized instruments to identify chemical characteristics common to fentanyl compounds and distinguish between many unrelated molecules that share the molecular mass of fentanyl.
All fentanyls have a common basic chemistry, but laboratories can vary the surrounding chemical groups. “It’s like a Christmas tree – almost always some kind of pine, but every home will decorate it differently,” Metz says. The instruments provide clues about the precise elements that make up molecules, how they are structured and the shape they take during analysis.
Now that the researchers knew what measurements would allow fentanyls to be thoroughly profiled, they came up with a database of hypothetical variants for the new study. They computer-split each of the approximately 60,000 known fentanyl and fentanyl-like molecules into a few different fragments, then recombined them to create several billion molecules. Next, they eliminated absurd and implausible molecules from their digital catalog, such as those that are unlikely to penetrate the brain’s protective barrier. Finally, with the help of machine learning, they predicted what actual chemical measurements of the imagined structures would look like. They combined this data with that of the 60,000 known structures to create their final digital library of more than a billion analogues.
The researchers couldn’t test for illicit drugs, so they created a fake fentanyl pill containing traces of 12 commercially available varieties of fentanyl, as well as a chemically similar non-opioid decoy, laced with ingredients typical of illicit pills like caffeine. They performed the feature identification measurements, then handed the raw data and computer-generated library to another analytical chemist who had never seen the fake pill, with a message: “We suspect there is fentanyl in this sample. Can you tell us what analogues, if any, are in it?”
The answer was a resounding “Yes”. After several rounds of narrowing down possible matches, the blind chemist perfectly identified six of the fake pill’s fentanyl components and narrowed four others down to a few possible candidates each, no library of pure compounds needed. The other two did not have the signatures used for reporting or could not be completely separated. The results have not yet been peer-reviewed.
The approach is a “great first step,” but it relies on custom instruments that aren’t available in most forensic or national security labs, says chemist A. Way Fountain III of the University of South Carolina at Columbia, who was not involved in the study. And the technique should be tested with other classes of drugs or molecules to show where improvements are needed, Fountain says.
Such tests are underway. Among several classes of molecules studied by Metz and colleagues, they also identified common features in a new family of laboratory-made opioids called nitazenes that become prevalent in overdose cases.
Wishart believes this work will help modernize the forensic community’s approach to identifying unknown compounds. Relying on a reference library of pure compounds “is still very 19th century thinking,” he says.
Molecular pharmacologist Gary Miller of Columbia University, who was not involved in the research, agrees. “Reference-free identification could be scientifically revolutionary,” he says. “This data demonstrates that this approach can work. »
