Withdrawal worse when fentanyl paired with animal tranquilizer

The rise in fentanyl use and overdose deaths became even more alarming recently when authorities found fentanyl laced with the animal tranquilizer xylazine. Some addiction specialists and public health officials feared the added xylazine would impede the fast-acting effects of the drug naloxone, which can effectively treat patients experiencing respiratory depression — a serious side effect of opioid use that can lead to death.

In a recent research discovery published in the journal Addiction Neuroscience, scientists at UNC-Chapel Hill found that xylazine activates opioid receptors in the brain in the same way fentanyl does. This finding could hint as to why withdrawal from fentanyl combined with xylazine is so severe.

This research, led by the lab of  Zoe McElligott, associate professor of psychiatry and pharmacology at the UNC School of Medicine, provides important insights into the subtle cellular mechanisms underlying opioid use — especially in light of the added anesthetic xylazine to fentanyl — and naloxone, the leading treatment used to prevent death from fentanyl overdose. McElligott is senior author of the paper, with co-first authors graduate student Madigan Bedard and assistant professor Xi-Ping Huang.

“Many people thought xylazine operated exclusively through a different mechanism in the nervous system,” said McElligott, also a member of the UNC Bowles Center for Alcohol Studies. “We may have gleaned insight into why withdrawal from the combination of fentanyl and xylazine is so harsh.”

People often choose to continue using drugs avoid the intense physical and psychological effects of withdrawal, according to McElligott. Her lab’s discovery, accomplished in collaboration with other UNC-Chapel Hill researchers, could have big implications for how clinicians might treat patients in the future.

“A big take-home message is that we want to make sure people are administered naloxone as a life-saving treatment,” McElligott said. “We don’t want people to not administer naloxone because they suspect someone has xylazine in their system.”

The study began in January 2023, when pharmacology graduate student Madigan Bedard poked her head into McElligott’s office and asked if she had heard that people were combining fentanyl with xylazine, an animal sedative.

“I was blown away,” McElligott said. She was interested because she studies the effects of withdrawal, and withdrawal from fentanyl/xylazine is particularly bad. She wanted to find out how the drug combination was affecting the brain.

They set up a strategic dosing experiment to study withdrawal in mice that received saline as a control, or fentanyl, fentanyl/xylazine. To be extra rigorous, Bedard set up an additional control looking at xylazine alone. Surprisingly, the xylazine mice treated with naloxone had major withdrawal symptoms.

To understand the results, the lab sought help from Dr. Bryan L. Roth, the Michael Hooker Distinguished Professor of Pharmacology who runs the NIH Psychoactive Drug Screening Program from his lab at the UNC School of Medicine. His team ran a rapid screen to see what receptors xylazine might target. A week later, Roth showed them the data. The drug latches on to kappa opioid receptors.

The unapproved use of xylazine in humans not only poses challenges for scientific and clinical understanding of the drug but also for those who work daily to navigate the adverse effects of the unregulated drug supply.

“The research being conducted in the McElligott Lab at UNC is of timely importance to legislators and regulatory agencies, such as the FDA, in their continued efforts to combat America’s opioid epidemic,” said Christin Daniels, executive director of the Triangle Center of Excellence in Regulatory Science and Innovation. “Until we have more data on the pharmacology, addictive properties and physiological effects, decisions about how to regulate xylazine are pending.”

Read more about the McElligott Lab study.