Fentanyl and Xylazine: Why Breathing Fails in Overdose

Watch Episode 172

The Bigger Picture: GPCR Science Meets Public Health

At its core, Catherine Demery’s research is about receptors and signaling pathways—how mu-opioid and alpha-2 adrenergic receptors interact to disrupt breathing. But it’s also about public health urgency.

Her findings highlight how fentanyl suppresses inhalation while xylazine prolongs exhalation, creating a respiratory cycle that collapses from both ends. The combination is not merely additive; it’s synergistic, shrinking tidal volume even when breathing rate appears stable.

The real killer, however, is apnea—those silent pauses where oxygen saturation crashes, often missed by surface-level monitoring. And because naloxone cannot reverse xylazine, the interventions that once worked for opioid overdoses are no longer enough.

With street-level contamination rising faster than medicine can adapt, Catherine’s work shows why overdose research must evolve alongside the drug supply.

For scientists, this means rethinking how we study GPCR-mediated respiratory depression. For clinicians, it’s a warning to update how we detect and respond to overdose. And for policymakers, it’s a stark reminder: the U.S. no longer faces a “fentanyl crisis”—it faces a polysubstance crisis.

A Crisis That’s Redefining Overdose

In 2023, more than 107,000 Americans died from drug overdoses, the highest number on record. Fentanyl was implicated in the vast majority of those deaths. Yet fentanyl is increasingly not alone.

Xylazine, a veterinary sedative never intended for human use, is infiltrating the opioid supply in cities and rural areas alike. In states such as Michigan and Pennsylvania, it has been detected in more than one in four fentanyl-related deaths.

This new pairing is uniquely dangerous. Fentanyl acts with devastating potency at the mu-opioid receptor, while xylazine exerts sedative effects through a different system altogether. And because naloxone only targets opioids, it cannot reverse xylazine. That gap leaves clinicians, first responders, and families without a reliable lifesaving tool in mixed overdoses.

Catherine’s research confronts this problem head-on by asking: What actually happens to breathing when these two drugs collide?

Mechanisms That Kill: The Double Hit to Breathing

Using whole-body plethysmography and pulse oximetry, Catherine studies how mice respond to fentanyl, xylazine, and their combination.

The results show a double assault on the respiratory cycle. Fentanyl, through the mu-opioid receptor, blunts the brainstem’s inspiratory drive so that each breath draws in less air.

Xylazine, acting through alpha-2 adrenergic receptors, slows the expiratory phase, making it harder to clear air out.

On their own, each drug weakens breathing. Together, they don’t just accumulate—they potentiate.

“When I combined the two drugs, there was a potentiation of fentanyl’s effect on tidal volume—mice were bringing in even less air,” Catherine explains.

This means overdose is not just about “slowed breathing.” It’s about a fundamental collapse of the cycle itself: one drug blocking air from entering, the other delaying its release.

Why Oxygen Monitors Can Miss the Danger

Perhaps the most unsettling part of Catherine’s work is the disconnect between breathing changes and oxygen saturation.

With fentanyl, the danger lies in apneas—complete pauses in breathing. Even if the respiratory rate doesn’t appear drastically lower, those pauses send oxygen levels plummeting.

By contrast, xylazine causes pronounced slowing of the breathing rate but fewer apneas, which means oxygen saturation doesn’t always drop as quickly.

This mismatch creates a dangerous blind spot. A patient might appear stable on an oxygen monitor, even as their breathing mechanics are deteriorating.

For emergency responders, this insight is critical: oxygen saturation alone is not always a reliable measure of overdose severity, especially in polysubstance cases.

Naloxone’s Limits in the Age of Xylazine

For decades, naloxone has been the trusted antidote for opioid overdoses. By displacing opioids from the mu-opioid receptor, it restores breathing within minutes. But that mechanism has no impact on xylazine, which works through alpha-2 adrenergic receptors.

The result is a growing number of cases where overdose victims respond partially to naloxone—they breathe a little better—but remain dangerously sedated, unresponsive, or relapse into respiratory depression. First responders describe revivals that don’t feel like revivals, as if the body is still trapped in a pharmacological fog.

Without a reversal agent for xylazine, the best defense right now is mechanistic understanding. Catherine’s work lays the foundation for designing better interventions, from preclinical models to clinical practice.

From Street Samples to Lab Models

What makes Catherine’s research particularly powerful is how it stays connected to reality outside the lab.

By collaborating with harm-reduction groups such as the Red Project in Grand Rapids, she ensures her models reflect the drugs people are actually using.

Those groups are reporting alarming trends: in Grand Rapids alone, the number of fentanyl samples containing xylazine has risen 30 to 60 percent in just a year. That surge mirrors what’s happening nationally. For Catherine, those numbers aren’t just statistics—they’re signals guiding how to build better models of polysubstance exposure.

The insight is simple but urgent: the drug supply evolves faster than medicine. Without research that keeps pace, clinical tools will always be one step behind.

Why This Research Matters Beyond the Lab

Catherine’s findings bridge the gap between basic receptor biology and real-world overdose response. For scientists, they sharpen our understanding of how different GPCR systems interact to produce respiratory depression. For clinicians, they challenge the assumption that oxygen monitors and naloxone alone are sufficient for managing overdoses. And for policymakers, they make clear that public health strategies must address polysubstance exposure, not just fentanyl in isolation.

In other words, this is GPCR science with immediate, life-or-death consequences.

The Urgency Ahead

Every overdose today is more complicated than the last. Breathing doesn’t fail in a single, predictable way—it collapses through overlapping pathways that no single drug can reverse. Monitoring tools miss critical warning signs. And the illicit supply is moving faster than clinical medicine can adjust.

That is why Catherine’s work matters: it shows in mechanistic detail how fentanyl and xylazine change what overdose even means. By tracing those pathways, her research gives scientists, first responders, and policymakers the knowledge they need to adapt—before the death toll climbs even higher.

“Fentanyl and xylazine aren’t just statistics. They’re rewriting the biology of overdose. The question now is whether science and public health can keep up.”