A potential antidote for the Fentanyl-Xylazine crisis

In recent years, fentanyl has become a household word, not because anyone wants it to be, but because it has reshaped the opioid crisis. This synthetic opioid is so potent that just a few grains can be fatal. Naloxone, better known by its brand name Narcan, has been the lifeline that first responders, families, and communities rely on to pull people back from the brink of overdose.

But a new player has entered the scene: xylazine, a veterinary sedative sometimes called “tranq.” Originally developed to calm horses and other large animals, xylazine has found its way into the illicit drug supply, often mixed with fentanyl. In 2023, the U.S. Drug Enforcement Administration reported that nearly a third of seized fentanyl powder contained xylazine. Tragically, this dangerous combination is making overdoses harder to reverse.

The U.S. recorded over 100,000 overdose deaths last year, with fentanyl involved in most of them. Adding xylazine to the mix has created what some call a “crisis within a crisis.” Not only does it raise the risk of death, but it also causes horrific skin ulcers in people who inject it and makes overdoses more stubbornly resistant to naloxone.

That’s where a team of scientists from Marshall University in Huntington, West Virginia comes in. In a new study published in [The Journal of Translational Research], researchers Jyostna Yalakala, Wesley R. Tackett, Melinda E. Varney, Todd H. Davies, and Michael D. Hambuchen tested a potential new antidote strategy. Their idea? Use a two-drug rescue approach, pairing the familiar naloxone with a lesser-known drug called atipamezole.

When naloxone is given during a fentanyl overdose, it blocks the opioid’s grip on the brain and allows the person to breathe again. But naloxone doesn’t touch xylazine. That means that in a fentanyl–xylazine overdose, a patient may regain some breathing but remain deeply sedated, with dangerously slowed heart rate, low blood sugar, and unstable body temperature.

In other words, naloxone alone is like fighting a two-headed dragon with a sword that only cuts one head. The other head, xylazine, keeps roaring.

This is where atipamezole comes in. Already used in veterinary medicine to wake animals up after anesthesia, atipamezole works by blocking the same receptors xylazine activates. The Marshall University team wondered: Could combining naloxone and atipamezole fight both fentanyl and xylazine at once?

The researchers carried out their experiments in male Sprague Dawley rats, a common laboratory model. They first determined how much fentanyl and xylazine together would cause severe sedation, mimicking the “heavy nod” seen in humans after using contaminated drugs.

When they gave naloxone alone, the rats perked up a bit but remained sluggish and dangerously affected. But when the team added atipamezole, sedation lifted dramatically, and rats given the combination became alert much faster. Also, the results showed that slow heart rate reversed. In fact, at higher doses, atipamezole normalized the heartbeat. Another effect was that atipamezole corrected high blood sugar, which is a side effect of xylazine that can stress the body. And finally, low body temperature improved, though not completely.

In short, the naloxone–atipamezole duo worked far better than naloxone alone.

The team also looked at what happens when methamphetamine, another drug often found in street mixtures, enters the picture. They found that at lower doses, atipamezole didn’t make meth’s jittery effects worse. But at higher doses, it could amplify stimulant-driven hyperactivity. That means careful dosing would be essential if this ever moves to human treatment.

The findings from Marshall University don’t mean we’ve found a ready-made cure. But they offer a proof of concept: if you want to fight a two-drug overdose, you may need a two-drug reversal.

Atipamezole is not currently approved for human use, it’s licensed only for animals. But because it has already been studied in small human trials (for other purposes) and was generally well tolerated, researchers are cautiously optimistic.

This study and its results bring the hope that, in the future, when a paramedic encounters someone who has overdosed on fentanyl laced with xylazine, they don’t just have naloxone in their kit, they also have a second medication that wakes the patient fully, stabilizes their heartbeat, and prevents dangerous lingering sedation. That future isn’t here yet, but thanks to this study, it feels a little closer. Science can’t solve the overdose crisis alone, prevention, treatment, and harm reduction are all essential, but better rescue tools could mean thousands more lives saved.

If you want to learn more, read the original article titled "Co-administration of naloxone and atipamezole to simultaneously reverse the acute effects of fentanyl and xylazine in rats" on Journal of Translational Research at http://dx.doi.org/10.1080/29947448.2025.2493044.