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Longer observation periods following treatment and safety considerations for chronic and frequent users are among the many research issues about xylazine-laced fentanyl that need addressing, Rachel Wightman, MD, said at a meeting on mitigating risks from human xylazine exposure sponsored by the Reagan-Udall Foundation.

"I take care of patients that are using fentanyl 10 plus times a day," Wightman, who is associate professor of emergency medicine and epidemiology at Brown University, in Providence, Rhode Island. "I have patients that wake up in the middle of the night in active withdrawal and have to use overnight to just get some sleep. And I guess the question is, are we enrolling those individuals in clinical trials?"

"I've seen protocols for novel therapeutics that are specifically trying to target populations using fentanyl," she added. "And in those study protocols, they have zero plans to actually enroll any individuals with active fentanyl use."

Xylazine, a tranquilizer, was approved by the FDA for veterinary use in 1932, but has never been approved for human use. However, it has been increasingly found in other drugs, especially fentanyl.

The consequences of xylazine use can be severe, Rahul Gupta, MD, director of the White House Office of National Drug Control Policy (ONDCP), said in April when he declared xylazine-laced fentanyl to be an "emerging drug threat."

"Its use, witting or unwitting, can result in serious and life-threatening effects, including death," he said. "A powerful sedative, xylazine slows breathing and heart rate, lowers blood pressure to unsafe levels, and complicates efforts to reverse opioid overdoses with naloxone. It produces deep flesh wounds in users that require extensive medical intervention and often admission to the intensive care unit. And it can also lead to amputation of limbs."

The National Institute on Drug Abuse (NIDA) is looking for more xylazine trials to fund and has seeking grant applications, Jane Acri, PhD, acting deputy director of NIDA's Division of Therapeutics and Medical Consequences, said at Wednesday's event. "We're calling for more research on xylazine pharmacology, physiological effects, clinical manifestations, the impact of xylazine on opioid overdose, outcomes for chronic xylazine exposure, assessment of potential pharmacotherapeutics, patterns of xylazine use -- including seeking xylazine versus avoiding xylazine -- xylazine presence in the drug supply, and psychosocial consequences of xylazine exposure."

Acri expressed excitement about one potential reversal drug -- CS-1103 -- that's currently undergoing animal testing. "Researchers have shown that IV administration of CS-1103 can increase xylazine clearance by six-fold in a 2-hour period in rats, and that it can accelerate emergence from sedation by three-fold, going from 46 minutes to 16 minutes -- again, in rats," she said. "It also works when fentanyl is present, reversing both respiratory depression and sedation."

"The compound is moving forward into first-in-man clinical trials, hopefully, in 2024," Acri added. "And this, I think, has the potential to be a game-changer when and if it becomes clinically available, to provide another kind of treatment option."

Meeting attendees also heard from Martin Lina Alcaraz, a former xylazine addict who is currently a peer educator at a buprenorphine clinic in Puerto Rico. "I was abusing substances for over 30 years; I was using xylazine for approximately 4 or 5 years of [that time]," Alcaraz said through a translator. "Those of us that used this substance realized the drastic difference when we used this versus other substances ... When I started to use this drug, I literally lost consciousness. It was very hard for a person to stop using that substance."

"[After] we started to use this 'horse anesthesia,' you couldn't use regular heroin" any more, Alcaraz said, referring to heroin without xylazine added. "You didn't feel the kick." He said the drug's addictiveness became especially apparent one day when local law enforcement was doing drug busts and he couldn't get to his usual dealer, so he tried to find somewhere else to buy it. "That's where I realized that this is not working" and it was getting too addictive, he said. On another day, he woke up after using only after a young girl -- a fellow addict -- "was slapping me across the face because I was on top of an anthill, and my whole face was completely covered by ants and they were biting me all over and I didn't feel anything. If it wasn't for that girl, God only knows what would have happened to me."

Xylazine caused so many problems in Puerto Rico that users -- including those who were incarcerated -- rebelled against the dealers who were addicting them, he said. "The leadership within the jail started to write communiques to people that had control of the drug sales in Puerto Rico to tell them that any person that was introducing 'horse anesthesia' to these points of sale, they were going to really suffer when they got to jail. That's how we were able to deal with this issue."

Luis Roman, PsyD, a clinical psychologist at Intercambios, a social services organization in Puerto Rico, urged attendees to think about meeting substance use disorder (SUD) patients where they are -- literally. "It's important we begin to organize as communities giving service in the streets," he said. "Federally qualified health centers receive a lot of funds and they have state-of-the-art treatment, but they're not going to where the people are. When you have substance use disorder, you have withdrawal symptoms, craving, and compulsive behavior. All of your day is spent buying and using the drug. You're not interested in going to a primary care doctor because you're deep into substance use disorder."

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