CATR: You have been active in the National Drug Early Warning System (NDEWS). Can you briefly describe that work?
Dr. Palamar: We track trends in drug use and related harms across the US, with particular attention to new and emerging substances. We focus on getting timely information rather than waiting for national reports. Our data come from a network of local partners around the country, alongside sources providing data almost in real time (emergency medical services, poison centers, drug seizure reports). The goal is to identify concerning trends early and alert communities so they can respond.

CATR: What illicit drugs are most encountered currently?
Dr. Palamar: Cannabis remains the most prevalent illicit drug, though its legal status and patterns of use continue to evolve, particularly with vaping and edibles. Cocaine and methamphetamine remain widely used. My work is more focused on emerging trends and novel psychoactive substances. The most consequential shift has been the evolution of the opioid crisis. Illicit fentanyl and its analogs are now the dominant drivers of drug-related deaths in the US. Even with recent reports of modest declines, deaths have been extraordinarily high, with roughly 70,000 per year in recent years (www.tinyurl.com/dxpe7hpr). Fentanyl is rarely the only substance involved: It is increasingly found mixed with other drugs, substantially compounding overdose risk.

CATR: What kinds of substances are you seeing mixed in with fentanyl?
Dr. Palamar: Broadly, these additives fall into two categories: opioids and non-opioids. The opioid additives tend to be highly potent synthetic opioids, including fentanyl analogs and nitazenes. The non-opioid additives span a wide range of drug classes with very different mechanisms of action and adverse effect profiles. Most of these are not controlled substances and include xylazine, medetomidine, and local anesthetics.

CATR: How did fentanyl come to dominate the opioid supply?
Dr. Palamar: About a decade ago, most illicit fentanyl exposure was unintentional. It was added to heroin to increase potency without disclosure. People believed they were using heroin when they were actually using fentanyl. That drove a sharp rise in overdose deaths and built tolerance; over time, many people started needing fentanyl to feel opioid effects. Although initially avoided by some users, within a year or two many began actively seeking it out for its potency. That market pressure has steadily pushed the supply toward ever more potent and dangerous opioids.

CATR: And that process has now moved beyond fentanyl itself.
Dr. Palamar: In many markets, fentanyl now has near-universal prevalence in the opioid supply. The growing concern is fentanyl analogs, compounds with varying and sometimes extremely high potency. Carfentanil, roughly 100 times more potent than fentanyl, largely disappeared for a period but has re-emerged. Also concerning are nitazenes, a distinct class of synthetic opioids built on a different molecular scaffold. Potency varies widely across nitazenes: Some are comparable to fentanyl, others are dozens of times stronger, and a few approach the potency of carfentanil.

CATR: When did nitazenes begin to appear in the US drug supply?
Dr. Palamar: They were detected sporadically decades ago, but around 2019 we began seeing them more frequently in the US. They are not yet as widespread as fentanyl, but their presence grew through 2024. Deaths involving nitazenes have increased, and the family of nitazene compounds that we are seeing is continuing to grow and change. However, it does appear that nitazene availability has recently begun to decrease.

CATR: Fentanyl analogs and nitazenes have been found in non-opioid drugs as well.
Dr. Palamar: Yes, which is another concerning trend. Drugs like cocaine, methamphetamine, and counterfeit benzodiazepine pills are often used by opioid-naïve individuals (including those who use drugs only intermittently or socially), putting them at elevated overdose risk. Fentanyl was the first opioid found adulterating these drugs, but nitazenes are now appearing beyond the opioid supply as well. They are most commonly detected in the fentanyl supply but have also appeared in illicit benzodiazepines, particularly counterfeit pills made to resemble alprazolam.

“These are new and unpredictable combinations, and people rarely know what they’re getting. That uncertainty increases risk across the board.”

Joseph Palamar, PhD 

CATR: How common is fentanyl exposure in settings like nightlife or party scenes?
Dr. Palamar: We are actively studying this. In New York City, for example, we are conducting saliva testing in nightclub settings. Most individuals in those environments do not test positive for fentanyl even though they may be using other illicit substances, suggesting exposure risk is not universal. However, overdose patterns indicate that geography plays a major role. In certain regions, particularly some low-income urban neighborhoods, drug distribution networks may differ in ways that increase the likelihood of fentanyl adulteration. Understanding those localized patterns remains an ongoing challenge.

CATR: Which non-opioid additives should clinicians be aware of?
Dr. Palamar: Xylazine is the most widely recognized example. It is a potent alpha-2 agonist that has been widely used as a veterinary sedative. When combined with fentanyl, it can cause profound and prolonged sedation. Naloxone can reverse the opioid component of an overdose, but it does not reverse the effects of xylazine, so patients may remain unresponsive even after naloxone administration. Another major concern is the severe peripheral wounds sometimes associated with repeated xylazine exposure. These wounds can be painful, rapidly progressive, and difficult to treat, creating additional morbidity beyond the obvious overdose risk (Editor’s note: For more on xylazine and peripheral wounds, see CATR Apr/May/Jun 2025).

CATR: Xylazine isn’t the only alpha-2 agonist appearing in the drug supply.
Dr. Palamar: Another emerging alpha-2 agonist we’re seeing increasingly is medetomidine—also a veterinary sedative, but with a potency 200–300 times greater than xylazine (Zhu DT and Palamar JJ, Lancet Reg Health Am 2025;44:101053). Many clinicians are familiar with clonidine, which also has alpha-2 activity, but medetomidine is far more receptor-selective and potent. In fact, it’s similar to dexmedetomidine, the rapid sedative used by anesthesiologists. Though not yet as widespread as xylazine, medetomidine is likely to continue spreading geographically over time.

CATR: What other unexpected substances are appearing in the opioid supply?
Dr. Palamar: One surprising finding has been the presence of local anesthetics, such as procaine and lidocaine, which I sometimes refer to as “the -caines.” This is not entirely new; decades ago, heroin in some regions commonly contained local anesthetics. They may be added to produce a numbing sensation or simply as fillers. What is new is how frequently we are seeing them, sometimes with multiple anesthetics present in a single sample, raising concerns about systemic toxicity. Ingesting local anesthetics can lead to seizures, arrhythmias, and unstable vital signs, which adds another layer of risk on top of opioid toxicity.

CATR: Are there other emerging additives clinicians should know about?
Dr. Palamar: More recently, we’ve started hearing about ketamine being mixed into fentanyl. When I first heard about it, I assumed ketamine was being adulterated with fentanyl. But it seems that the opposite is the case—fentanyl is being adulterated with ketamine as a filler in some samples. This tends to be mostly in urban areas, at least for now, but that could change.

CATR: This is quite the laundry list of possible contaminants. Any others to add?
Dr. Palamar: One more emerging concern is industrial chemicals appearing in drug samples without appreciable psychoactive effects. An example is BTMPS, used in plastic manufacturing, which has been detected in fentanyl samples across multiple states, suggesting upstream contamination. Users have described a burning plastic odor and systemic symptoms, and animal studies suggest possible cardiotoxicity, eye damage, and even sudden death (Shover CL et al, JAMA 2025;333(11):1000–1003). These findings illustrate how rapidly the drug supply is evolving. The mixtures keep changing, with new combinations that users rarely see coming, and that uncertainty increases risk across the board.

CATR: Given such an unpredictable drug supply, it can be difficult to tell what a patient has ingested, especially in an emergency setting. What advice would you give clinicians when treating patients who have ingested unknown substances?
Dr. Palamar: An emergency medicine colleague once said, “We don’t treat the drug; we treat the symptom.” That principle has always resonated with me. If a presentation suggests opioid overdose, naloxone should be given. Beyond that, management should be guided by the patient’s clinical status: Airway, breathing, circulation, and hemodynamic stability should drive decision-making. Stabilization and prompt hospital care are priorities with any concern for respiratory depression or altered consciousness.

CATR: What are the geographic patterns clinicians should be aware of?
Dr. Palamar: Trends tend to follow the same geographic pattern over and over again; new drugs or mixtures emerge in a specific urban area and then spread outward. Fentanyl initially took hold in Northeastern cities before becoming ubiquitous nationwide. Xylazine was first concentrated around Philadelphia before expanding to other regions. Some substances remain localized for extended periods. For example, certain synthetic cathinones currently detected in New York City have not yet appeared elsewhere. This means alerts and clinical awareness need to be regionally tailored. Even neighboring states can have very different drug supplies.

CATR: So how can clinicians stay current with what is happening locally, especially given how rapidly the drug supply changes?
Dr. Palamar: It can be a challenge. Trends are regional, so your local public health department can be an important resource. Many areas also have drug checking organizations that distribute regular alerts. NDEWS is another valuable tool. We track drug trends nationwide and publish weekly briefings every Friday (www.tinyurl.com/48vax266). These updates provide timely information on emerging substances and regional patterns, which can help clinicians stay informed as the drug supply evolves.

CATR: What role does drug checking play in all this?
Dr. Palamar: Giving patients the ability to check their own drugs, typically with immunoassay test strips, remains an important tool. Fentanyl test strips have been widely available for years at this point, and xylazine test strips are also available and have been well validated (Jones S and Bailey S, Canadian Agency for Drugs and Technologies in Health 2023; Report No: EN0049). Nitazene test strips exist as well, although their reliability could be more limited. At this time, I am not aware of test strips for local anesthetics. There are also drug checking organizations that play a critical role by combining field testing with advanced laboratory analysis. These groups are essential for identifying emerging trends and issuing timely public health alerts.

CATR: Overdose deaths have recently declined for the first time in years. What do you think is driving that change?
Dr. Palamar: There were meaningful declines in overdose death rates in 2023 and 2024, though the reasons are not fully understood. Expanded naloxone availability has saved many lives, and getting naloxone into as many hands as possible remains essential. But we need to look at the data critically. Part of the reduction may reflect that many of the highest-risk individuals have already died, meaning overall deaths can decline without a corresponding reduction in risk among those still using. Reducing harm remains important, but we must continue to emphasize prevention and treatment.

CATR: Thank you for your time, Dr. Palamar.