Fighting Fentanyl Overdose

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Prince in 2016, Tom Petty in 2017, Coolio in 2022. Three American music megastars who, along with an infant at a New York daycare facility and hundreds of thousands of other Americans who didn’t make the news, died from accidental overdose of the synthetic opioid fentanyl. Last year alone, more than 115 million illegal fentanyl pills were seized by U.S. law enforcement, yet enough remained on the streets that nearly 75 thousand people got a lethal dose. That’s more than 200 people per day, or one fentanyl fatality every 7 minutes.

Fentanyl is a legal but tightly controlled prescription painkiller. But illicit fentanyl, the knockoff version, is the number one cause of overdose deaths in the United States. It is smuggled into the country by air from Asia and by land from Mexico, hidden in modest packages of otherwise benign contents, like food or toys, and then, once in, it’s unleashed into the street-drug market. Catching it at ports of entry is costly and time consuming. Typically, x-ray systems are used to flag anomalies, like hidden compartments in vehicles, then any package that is found and deemed suspicious is opened and the contents analyzed with special spectroscopic or chemical tests. To help break the supply chain of this lethal drug, a Los Alamos team is developing an instrument that can screen packages for fentanyl quickly and reliably without even opening them.

Illicit fentanyl is the number one cause of drug overdose deaths in the United States. 

There are two roads to a fentanyl overdose: First, fentanyl is sometimes intentionally overconsumed or mixed with other drugs, creating unanticipated toxic interactions. Second, and more commonly, it is overconsumed unintentionally because it’s hidden within a different drug and the consumer doesn’t know it’s there. Fentanyl is cheap and easy to make compared to other street drugs. Traffickers routinely stretch a more expensive product, like heroin or cocaine, by first bulking it up with something like aspirin or baby powder, then spiking it with a bit of fentanyl to restore potency before selling it all as the more expensive original. But because of the very high strength of pure fentanyl powder, it’s hard to dilute precisely, so small inaccuracies in weight can cause huge variation between batches, and it’s all too easy for someone to get too much. For comparison, one teaspoon of sugar weighs 4200 milligrams, and just two milligrams of pure fentanyl is a potentially lethal dose.

Los Alamos has a broad national security mission, and the fentanyl crisis is a national security problem. According to the United States Drug Enforcement Agency (DEA), the fentanyl being spiked into street drugs is illicitly made primarily outside the United States where it’s easier to source the ingredients. Once smuggled in, illicit fentanyl is either passed off as the real deal or mixed into other drugs to drive addiction. Either way, it reaches every corner of the country with tragic results: In the two decades from 2003 to 2023, nearly half a million people died as the rate of fatal fentanyl overdose skyrocketed. The year 2003 saw 1400 fentanyl fatalities; in 2013, the annual count had more than doubled to 3100; another decade brought a 24-fold increase, with 74,702 deaths attributed to fentanyl overdose in 2023. To put that into perspective, that’s more than the entire Vietnam War in just a single year. (The Vietnam War caused 58,281 American fatalities over its nearly 20-year duration, while fentanyl has so far caused 432,738 over a similar timeframe).

“Pharmaceutical fentanyl being used illegally is one problem, but illicit fentanyl being made via garage chemistry is the bigger problem,” explains Los Alamos physicist Michael Malone, who leads the fentanyl detector project. “The nightmare reality is that synthesis can be tweaked to escape compound-specific detection.” Malone and his team of about a dozen scientists are therefore developing their detector to be not only fast, but also less compound-specific and thus less easily evaded.

Facts about fentanyl

The label “fentanyl” actually covers a whole family of closely related synthetic opioids. Opioids are a class of drugs derived from the opium poppy, a plant native to the Eastern Mediterranean. Opium, the original opioid, has been used by people for thousands of years for medical, religious, and recreational purposes. It’s said to create feelings of euphoria. Other natural opioids include morphine, codeine, and heroin, all of which, like opium, have long been known to be highly addictive. Synthetic opioids were designed by chemists to mimic natural opioids in the hopes of developing pharmaceutical analgesics that were more effective and less addictive. The chemists succeeded in one of these goals: the drugs they designed are more effective than their natural counterparts, but fentanyl and other synthetic opioids like oxycodone, hydrocodone, and hydromorphone are also, as it turns out, extremely addictive.

Originally developed in Europe, pharmaceutical fentanyl has been legal in the United States for medical use since the 1960s and is presently prescribed over a million times a year. It is a DEA schedule II drug, meaning it is legal and has an accepted medical use, but access to it is controlled due to a high potential for abuse. It is considered one of the most important opioids for pain management because of its potency and flexibility: it is 100 times more powerful than morphine and can be administered orally, intravenously, transdermally, and transmucosally. It is often given to surgical patients and people with cancer, and in these medical settings where the dose is tightly controlled and the response is closely monitored, it is considered safe.

Illicit fentanyls, on the other hand, are all DEA schedule I drugs, meaning they are illegal to make, posses, or distribute and have no approved medical use and a high potential for abuse. But they’re relatively cheap and easy to make, and the demand is high, so the variety has flourished.

Continually changing the formulation is how the makers of illicit fentanyl manage to skirt detection. 

Fentanyls typically come as salts, that is, crystalline compounds formed from the ionic bonding of an anion and a cation, which has no net charge and is more stable than its constituent parts. “For example, sodium on its own violently reacts with water,” says Malone. “And chlorine by itself is nasty, too. But you put them together, and you get sodium chloride, or table salt, which is not only shelf-stable, but also an essential nutrient.”

For pharmaceutical fentanyl, the anion is a free fentanyl molecule (C₂₂H₂₈N₂O) and the cation is a citric acid molecule (C₆H₈O₇). For illicit fentanyls, the cation can be any of a number of different chemicals. Presently, one of the most common illicit fentanyls is fentanyl hydrochloride, in which a hydrochloric acid molecule (HCl) is the cation for the salt. (The term “freebase” refers to reversing this process by using a chemical base to remove the cation, taking apart the salt and freeing the pure, now more reactive, form of the drug.) This versatility in salt formulation is part of why there are so many different illicit fentanyl analogs and why they can be hard to detect with compound-specific methods.

Another contributing factor to the spectrum of illicit fentanyls is the many possible modifications of the free fentanyl molecule itself that can change its structure and potency. One grim example is carfentanil, which has an additional carboxylic acid group (CO₂H). This modification makes it 10,000 times more potent than morphine and 100 times more lethal in humans than pharmaceutical fentanyl citrate. The only legal use of carfentanil is as an elephant and rhinoceros tranquilizer, yet it is commonly abused and is a frequent factor in fatal overdose. Continually changing the salt formulation and chemical modifications based on ingredient availability and DEA loopholes is how the makers of illicit fentanyls manage to skirt detection of their products.

Regardless of salt formulation or chemical modifications, there are certain chemical motifs that all fentanyls share. For example, they all have at their core a piperidine group (C₅H₅N) bonded to an aniline group (C₆H₇N). This chemical core, in particular the aniline nitrogen atom, is the key to the detector that Malone and his team are developing. They want their detector to find all the different fentanyls, so they’re focusing on that common core. With such a device, any version of fentanyl, counterfeit or not, pill or powder, concealed or disguised—could be caught.

Resonance to the rescue

The team’s approach is centered around two different magnetic resonance techniques, nuclear magnetic resonance (NMR) and nuclear quadrupole resonance (NQR). (Neither technique involves ionizing radiation; the “nuclear” for both methods refers to interrogation of the atomic nucleus.) The fentanyl detector the team is building will use NQR when deployed, but it will be calibrated and validated in the lab by long-standing NMR techniques.

NMR is the better known of the two methods. Among other things, it enables magnetic resonance imaging, which is used in medical diagnosis of soft-tissue anomalies. But NMR itself is not an imaging method; it’s a chemical identification method that exploits the energy required to reorient the magnetic fields of atomic nuclei within an applied magnetic field.

Certain nuclei have their own magnetic fields, which, in the absence of an applied field, are randomly oriented. When an external magnetic field is applied, the magnetic fields of the nuclei preferentially align with it, resulting in a bulk magnetization of the material. Next, a pulse of alternating current (AC) radio-frequency energy is applied, causing the bulk magnetization to rotate, which produces an AC magnetic field. It’s this magnetic field that then gets detected with a magnetometer, which can be as simple as a coil of wire.

What makes this “resonant” is that the frequency, or the rate of oscillation, of the radio pulse is the same as the frequency of the resulting magnetic field, and it is proportional to the energy required to reorient the nuclei—so the larger the magnetic field, the larger the frequency. Neighboring nuclei produce enough local variation in the magnetic field to change the resonance frequency, which shows up in the NMR spectrum and allows determination of molecular structure—which atoms are present in the material and who is bonded to who.

NQR is similar to NMR, but differs in the details. Both techniques use resonant radio-frequency pulses to produce an AC magnetic field from the target nuclei. However, whereas NMR is based on the energy required to reorient small magnetic fields within a larger one, NQR is based on the energy required to reorient small electric charges within a larger electric field. It only works on nuclei with a nonspherical, or quadrupolar, charge distribution, and it only works in an electric field gradient, not a uniform electric field. These constraints mean NQR can only be performed on certain nuclei, namely quadrupolar nuclei, and for certain materials, namely crystalline solids.

More than 99 percent of nitrogen atoms in the world are of the isotope nitrogen-14, which is quadrupolar, making it an ideal target for NQR spectroscopy. Nitrogen-14-based NQR is proven for field settings, previously being used to detect explosives buried underground. The chemical core of all fentanyl analogs contains two nitrogen atoms, so it presents a perfect target for NQR detection.

Each fentanyl analog has a unique NQR frequency, so pinning one down doesn’t necessarily lead to the others. “Nitrogen NQR frequencies cover a wide range, and without prior structural or chemical information, they would be impossible to predict,” says Harris Mason, a Lab chemist on the team who leads the NMR portion of the project. “Solid-state NMR helps tell the NQR folks where to look. NQR gives nice, sharp, well-defined signal peaks that are perfect for fingerprinting, but you don’t know where to find them beforehand, and because they are so narrow, searching by NQR is a pain. It’s better to search first using NMR because the peaks are bigger and blobbier and harder to miss.”

In other words, the team uses NMR to zero in on the resonant frequencies, then NQR to do the actual detection. One advantage of using NQR for the detector is that the resonant frequencies are chemically unique, making it ideal for chemical detection. Also, NQR is more field-deployable than NMR.

NQR is often described as NMR without the magnet. “My Ph.D. advisor used to call NQR ‘poor man’s NMR’ because, according to him, it’s the technique you do when you can’t afford a magnet,” says Mason. “But, sometimes it isn’t about the cost, sometimes it’s infrastructure, deployability, or simply that NQR is adequate, and NMR isn’t necessary.”

The NQR-based detector system that the Los Alamos team has built currently consists of about 100 thousand dollars of specialized hardware. A powerful radio-frequency amplifier produces the pulses needed to excite the signal, and a specialized spectrometer controls the experiment and processes the data.

The detector should be able to interrogate a package about multiple fentanyls at once, with a high degree of confidence.

The goal, however, is a simplified and portable system consisting of a handheld device, about the size of a clothes iron, containing both the excitation and detection hardware, which is connected to a laptop computer that, along with two digital-analog signal converters, rides in a backpack worn by the user.

The order of operations is essentially this: the handheld unit is placed against a package, then a pulse of radio frequency, controlled by the laptop, is sent into the excitation coil in the handheld unit and the resulting magnetic field excites the nitrogen nuclei in the target. After the pulse, as the nitrogen nuclei relax back to thermal equilibrium, a magnetometer in the handheld unit detects the temporary magnetic field of the sample. The signal is sent to the laptop where it is quantified by special software, and finally the result is reported via colored lights on the handheld unit—red light means fentanyl is present, green light means it’s not.

Some NQR devices require cryogenic temperatures to get a clear reading, but the Los Alamos team needed a detector that operates at room temperature. What’s more, it had to be able to penetrate simple packaging, seeing straight through cardboard, plastic, glass, and even metallic foils, and it had to do it in under a minute.

“I wasn’t confident it would work. But it did, and the signal was surprisingly robust.”

In March 2024, after two years of work on the project, the Los Alamos scientists got the first ever NQR reading for any fentanyl analog, using their prototype device on fentanyl HCl.

“It was pretty cool,” says Malone, “because I wasn’t actually confident it would work. But it did, and the signal was surprisingly robust.”

The successful NQR reading was a big deal because it proved that an NQR-based fentanyl detector is possible, and it also filled a gap in the scientific understanding of these compounds. Now that the scientists have proven that their system works, it’s essentially back to the drawing board to examine different analogs, establish limitations, and determine efficacy.

Project pipeline

Each NQR signal is a narrow peak somewhere in a very wide spectral space, so unless one knows where to look, it can take a long time to find a signal, and it can be easily missed—like scanning a radio dial for weak or distant channels. The NQR frequencies for fentanyls, the precise frequencies of radio energy that will excite the nitrogen atoms within the molecules, were essentially unknown when the project began, so the Los Alamos team had to start at the very beginning, and the first step was to synthesize their own samples.

Physical organic chemist Bob Williams is in charge of chemical synthesis for the project. “If you know enough of the theory, you can do the computation,” he explains. “Computation then gives you a frequency range where to point your NMR, and NMR narrows it down and tells you where to point your NQR. But first you need pure samples of each analog so you can make good physical measurements.” Williams has a special license from the DEA to synthesize these compounds.

Some of the necessary physical measurements rely on knowing the crystal structure of the compound, so Laboratory chemist Aaron Tondreau produced a solid crystal of each analog. This allowed Tondreau to determine the compounds’ crystal structures via x-ray crystallography, which uses x-ray diffraction to determine the molecular structure of a pure crystalline compound. The method is particularly useful in differentiating closely related materials—like fentanyls—because it provides information about atomic positions, bond types, and bond lengths. These details then get fed back into the computations that predict NQR frequency.

So far, the Los Alamos team has a library of about 25 different fentanyl analogs, representing a variety of salt formulations and chemical modifications. Out of these, the team has solved the crystal structure of about a dozen, including fentanyl HCl—only pharmaceutical fentanyl citrate’s crystal structure was previously known. Using this in-house fentanyl library, the team is amassing NMR and NQR data and now has the largest known database of NQR parameters for synthetic opioids.

NQR signals are not only narrow in frequency, but in time as well. The detector is only looking for the aniline nitrogen, one of the two nitrogens in the fentanyl common core. As the nuclei return to thermal equilibrium, as they relax, the signal dies. You have to be looking at the right place at the right time—blink and you might miss it. To pin down the relaxation properties for the aniline nitrogen in each fentanyl analog, NMR expert Michelle Espy uses fast-field cycling NMR, a technique that uses an externally applied magnetic field, sweeping from low to high, to indirectly observe the NQR system’s relaxation rates by interrogating hydrogen nuclei that are coupled to the nitrogen system.

Finally, the team is also using a computational method, density functional theory (DFT), to learn about the physics of the molecule, particularly the electron density. NMR and NQR both measure the electron density close to the nucleus of an atom, and DFT, because it’s math on a supercomputer, helps see under the hood of both phenomena. The DFT work is led by materials scientist Ann Mattsson and will help the team distinguish between the two nitrogen atoms, for example, to be sure they’re measuring the aniline nitrogen. It can also help the team widen its net by computationally examining theoretical fentanyl analogs—ones that haven’t been encountered yet, but might be in the future—and suggesting what their NQR frequencies are likely to be.

Comprehensive coverage

Right now, the detector works like a game of Go Fish: Do you have fentanyl citrate? Do you have fentanyl hydrochloride? Do you have carfentanil? Each analog has a unique NQR frequency and the detector can only ask about one at a time. But the goal is to make it universal, or at least comprehensive. The next generation of detector should be able to interrogate a package about multiple fentanyls at once with a high degree of confidence.

The fentanyl problem in the united states cannot be overstated and it’s getting worse by the day.

It'll be kind of like the flu shot. Each year, the flu vaccine is designed to target whichever strains of circulating influenza virus are dominant in the population, but it can’t possibly cover every strain out there—indeed, it doesn’t need to. “It’s not realistic to include every single fentanyl analog,” explains Malone. “But 50 percent of the market would be great. We could adapt to the analogs that make up the bulk of street fentanyl as it changes over time.” So, by calibrating the detectors to the current most likely suspects, the scientists are confident in the coverage they’ll achieve.

With their growing library of NMR and NQR data and their increasingly refined mechanical device, the scientists are closing in on the ultimate goal: a practical detector that they hope to demonstrate to authorities within the U.S. Customs and Border Protection, the Department of Homeland Security, and other law enforcement agencies.

There are already scanners in place at many points of entry, some large enough to scan an entire car, looking for hidden compartments and clever disguises. But these scanners are x-ray-based, and don’t have any chemical specificity. They can show that something is there, but can’t determine what it is. Typically, the next step is to open the package and do hands-on testing. This is where the Los Alamos device would come in, replacing slow and costly hands-on testing with rapid and reliable diagnostics.

The fentanyl problem in the United States cannot be overstated, and it’s getting worse by the day. The solution must be to throw everything we’ve got at it: public information campaigns, improved access to treatment programs, distribution of medications that treat addiction and reverse overdose, whole-vehicle scanners at the border, and personnel trained to spot smuggling attempts. Soon, we’ll be able to add to that arsenal easy-to-use, science-based, broad-coverage detectors that will help take fentanyl off the nation’s streets.

People also ask

• What is the opioid crisis? An ongoing public health crisis beginning in the late 1990s, which has seen a drastic increase in the overuse of pain medication belonging to a class of drugs called opioids. Oxycodone, hydrocodone, and fentanyl are three opioids driving the crisis, being relatively easy to source and highly addictive. 
• What are the side effects of fentanyl? Acute side effects of fentanyl use include relaxation, euphoria, pain relief, sedation, confusion, drowsiness, dizziness, nausea and vomiting, urinary retention, pupillary constriction, and respiratory depression. 
• How much fentanyl does it take to overdose? The effective dose of fentanyl depends on body weight, mode of ingestion, and prior exposure. Just two milligrams of pure fentanyl is considered a potentially lethal dose and illicitly made pills often contain more than that.