TREASURE ISLAND, Fla. — Andrew McClave Jr. loved to lift weights. The 6-foot-4-inch bartender resembled a bodybuilder and once posed for a photo flexing his muscles with former pro wrestler Hulk Hogan.

“He was extremely dedicated to it,” said his father, Andrew McClave Sr., “to the point where it was almost like he missed his medication if he didn’t go.”

But the hobby took its toll. According to a police report, a friend told the Treasure Island Police Department that McClave, 36, suffered from back problems and took unprescribed pills to reduce the pain.

In late 2022, the friend discovered McClave in bed. He had no pulse. A medical examiner determined he had a fatal amount of fentanyl, cocaine, and xylazine, a veterinary tranquilizer used to sedate horses, in his system, an autopsy report said. Heart disease was listed as a contributing factor.

McClave is among more than 260 people across Florida who died in one year from accidental overdoses involving xylazine, according to a Tampa Bay Times analysis of medical examiner data from 2022, the first year state officials began tracking the substance. Numbers for 2023 haven’t been published.

The death toll reflects xylazine’s spread into the nation’s illicit drug supply. Federal regulators approved the tranquilizer for animals in the early 1970s and it’s used to sedate horses for procedures like oral exams and colic treatment, said Todd Holbrook, an equine medicine specialist at the University of Florida. Reports of people using xylazine emerged in Philadelphia, then the drug spread south and west.

What’s not clear is exactly what role the sedative plays in overdose deaths, because the Florida data shows no one fatally overdosed on xylazine alone. The painkiller fentanyl was partly to blame in all but two cases in which the veterinary drug was included as a cause of death, according to the Times analysis. Cocaine or alcohol played roles in the cases in which fentanyl was not involved.

Fentanyl is generally the “800-pound gorilla,” according to Lewis Nelson, chair of the emergency medicine department at Rutgers New Jersey Medical School, and xylazine may increase the risk of overdose, though not substantially.

But xylazine appears to complicate the response to opioid overdoses when they do happen and makes it harder to save people. Xylazine can slow breathing to dangerous levels, according to federal health officials, and it doesn’t respond to the overdose reversal drug naloxone, often known by the brand name Narcan. Part of the problem is that many people may not know they are taking the horse tranquilizer when they use other drugs, so they aren’t aware of the additional risks.

Lawmakers in Tallahassee made xylazine a Schedule 1 drug like heroin or ecstasy in 2016, and several other states including Pennsylvania, Ohio, and West Virginia have taken action to classify it as a scheduled substance, too. But it’s not prohibited at the federal level. Legislation pending in Congress would criminalize illicit xylazine use nationwide.

The White House in April designated the combination of fentanyl and xylazine, often called “tranq dope,” as an emerging drug threat. A study of 20 states and Washington, D.C., found that overdose deaths attributed to both illicit fentanyl and xylazine exploded from January 2019 to June 2022, jumping from 12 a month to 188.

“We really need to continue to be proactive,” said Amanda Bonham-Lovett, program director of a syringe exchange in St. Petersburg, “and not wait until this is a bigger issue.”

‘A Good Business Model’

There are few definitive answers about why xylazine use has spread — and its impact on people who consume it.

The U.S. Drug Enforcement Administration in September said the tranquilizer is entering the country in several ways, including from China and in fentanyl brought across the southwestern border. The Florida attorney general’s office is prosecuting an Orange County drug trafficking case that involves xylazine from a New Jersey supplier.

Bonham-Lovett, who runs IDEA Exchange Pinellas, the county’s anonymous needle exchange, said some local residents who use drugs are not seeking out xylazine — and don’t know they’re consuming it.

One theory is that dealers are mixing xylazine into fentanyl because it’s cheap and also affects the brain, Nelson said.

“It’s conceivable that if you add a psychoactive agent to the fentanyl, you can put less fentanyl in and still get the same kick,” he said. “It’s a good business model.”

In Florida, men accounted for three-quarters of fatal overdoses involving xylazine, according to the Times analysis. Almost 80% of those who died were white. The median age was 42.

Counties on Florida’s eastern coast saw the highest death tolls. Duval County topped the list with 46 overdoses. Tampa Bay recorded 19 fatalities.

Cocaine was also a cause in more than 80 cases, including McClave’s, the Times found. The DEA in 2018 warned of cocaine laced with fentanyl in Florida.

In McClave’s case, Treasure Island police found what appeared to be marijuana and a small plastic bag with white residue in his room, according to a police report. His family still questions how he took the powerful drugs and is grappling with his death.

He was an avid fisherman, catching snook and grouper in the Gulf of Mexico, said his sister, Ashley McClave. He dreamed of being a charter boat captain.

“I feel like I’ve lost everything,” his sister said. “My son won’t be able to learn how to fish from his uncle.”

Mysterious Wounds

Another vexing challenge for health officials is the link between chronic xylazine use and open wounds.

The wounds are showing up across Tampa Bay, needle exchange leaders said. The telltale sign is blackened, crusty tissue, Bonham-Lovett said. Though the injuries may start small — the size of a dime — they can grow and “take over someone’s whole limb,” she said.

Even those who snort fentanyl, instead of injecting it, can develop them. The phenomenon is unexplained, Nelson said, and is not seen in animals.

IDEA Exchange Pinellas has recorded at least 10 cases since opening last February, Bonham-Lovett said, and has a successful treatment plan. Staffers wash the wounds with soap and water, then dress them.

One person required hospitalization partly due to xylazine’s effects, Bonham-Lovett said. A 31-year-old St. Petersburg woman, who asked not to be named due to concerns over her safety and the stigma of drug use, said she was admitted to St. Anthony’s Hospital in 2023. The woman, who said she uses fentanyl daily, had a years-long staph infection resistant to some antibiotics, and a wound recently spread across half her thigh.

The woman hadn’t heard of xylazine until IDEA Exchange Pinellas told her about the drug. She’s thankful she found out in time to get care.

“I probably would have lost my leg,” she said.

This article was produced in partnership with the Tampa Bay Times.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

Subscribe to KFF Health News’ free Morning Briefing.

One January morning in 2021, Carol Rosen took a standard treatment for metastatic breast cancer. Three gruesome weeks later, she died in excruciating pain from the very drug meant to prolong her life.

Rosen, a 70-year-old retired schoolteacher, passed her final days in anguish, enduring severe diarrhea and nausea and terrible sores in her mouth that kept her from eating, drinking, and, eventually, speaking. Skin peeled off her body. Her kidneys and liver failed. “Your body burns from the inside out,” said Rosen’s daughter, Lindsay Murray, of Andover, Massachusetts.

Rosen was one of more than 275,000 cancer patients in the United States who are infused each year with fluorouracil, known as 5-FU, or, as in Rosen’s case, take a nearly identical drug in pill form called capecitabine. These common types of chemotherapy are no picnic for anyone, but for patients who are deficient in an enzyme that metabolizes the drugs, they can be torturous or deadly.

Those patients essentially overdose because the drugs stay in the body for hours rather than being quickly metabolized and excreted. The drugs kill an estimated 1 in 1,000 patients who take them — hundreds each year — and severely sicken or hospitalize 1 in 50. Doctors can test for the deficiency and get results within a week — and then either switch drugs or lower the dosage if patients have a genetic variant that carries risk.

Yet a recent survey found that only 3% of U.S. oncologists routinely order the tests before dosing patients with 5-FU or capecitabine. That’s because the most widely followed U.S. cancer treatment guidelines — issued by the National Comprehensive Cancer Network — don’t recommend preemptive testing.

The FDA added new warnings about the lethal risks of 5-FU to the drug’s label on March 21 following queries from KFF Health News about its policy. However, it did not require doctors to administer the test before prescribing the chemotherapy.

The agency, whose plan to expand its oversight of laboratory testing was the subject of a House hearing, also March 21, has said it could not endorse the 5-FU toxicity tests because it’s never reviewed them.

But the FDA at present does not review most diagnostic tests, said Daniel Hertz, an associate professor at the University of Michigan College of Pharmacy. For years, with other doctors and pharmacists, he has petitioned the FDA to put a black box warning on the drug’s label urging prescribers to test for the deficiency.

“FDA has responsibility to assure that drugs are used safely and effectively,” he said. The failure to warn, he said, “is an abdication of their responsibility.”

The update is “a small step in the right direction, but not the sea change we need,” he said.

Europe Ahead on Safety

British and European Union drug authorities have recommended the testing since 2020. A small but growing number of U.S. hospital systems, professional groups, and health advocates, including the American Cancer Society, also endorse routine testing. Most U.S. insurers, private and public, will cover the tests, which Medicare reimburses for $175, although tests may cost more depending on how many variants they screen for.

In its latest guidelines on colon cancer, the Cancer Network panel noted that not everyone with a risky gene variant gets sick from the drug, and that lower dosing for patients carrying such a variant could rob them of a cure or remission. Many doctors on the panel, including the University of Colorado oncologist Wells Messersmith, have said they have never witnessed a 5-FU death.

In European hospitals, the practice is to start patients with a half- or quarter-dose of 5-FU if tests show a patient is a poor metabolizer, then raise the dose if the patient responds well to the drug. Advocates for the approach say American oncology leaders are dragging their feet unnecessarily, and harming people in the process.

“I think it’s the intransigence of people sitting on these panels, the mindset of ‘We are oncologists, drugs are our tools, we don’t want to go looking for reasons not to use our tools,’” said Gabriel Brooks, an oncologist and researcher at the Dartmouth Cancer Center.

Oncologists are accustomed to chemotherapy’s toxicity and tend to have a “no pain, no gain” attitude, he said. 5-FU has been in use since the 1950s.

Yet “anybody who’s had a patient die like this will want to test everyone,” said Robert Diasio of the Mayo Clinic, who helped carry out major studies of the genetic deficiency in 1988.

Oncologists often deploy genetic tests to match tumors in cancer patients with the expensive drugs used to shrink them. But the same can’t always be said for gene tests aimed at improving safety, said Mark Fleury, policy director at the American Cancer Society’s Cancer Action Network.

When a test can show whether a new drug is appropriate, “there are a lot more forces aligned to ensure that testing is done,” he said. “The same stakeholders and forces are not involved” with a generic like 5-FU, first approved in 1962, and costing roughly $17 for a month’s treatment.

Oncology is not the only area in medicine in which scientific advances, many of them taxpayer-funded, lag in implementation. For instance, few cardiologists test patients before they go on Plavix, a brand name for the anti-blood-clotting agent clopidogrel, although it doesn’t prevent blood clots as it’s supposed to in a quarter of the 4 million Americans prescribed it each year. In 2021, the state of Hawaii won an $834 million judgment from drugmakers it accused of falsely advertising the drug as safe and effective for Native Hawaiians, more than half of whom lack the main enzyme to process clopidogrel.

The fluoropyrimidine enzyme deficiency numbers are smaller — and people with the deficiency aren’t at severe risk if they use topical cream forms of the drug for skin cancers. Yet even a single miserable, medically caused death was meaningful to the Dana-Farber Cancer Institute, where Carol Rosen was among more than 1,000 patients treated with fluoropyrimidine in 2021.

Her daughter was grief-stricken and furious after Rosen’s death. “I wanted to sue the hospital. I wanted to sue the oncologist,” Murray said. “But I realized that wasn’t what my mom would want.”

Instead, she wrote Dana-Farber’s chief quality officer, Joe Jacobson, urging routine testing. He responded the same day, and the hospital quickly adopted a testing system that now covers more than 90% of prospective fluoropyrimidine patients. About 50 patients with risky variants were detected in the first 10 months, Jacobson said.

Dana-Farber uses a Mayo Clinic test that searches for eight potentially dangerous variants of the relevant gene. Veterans Affairs hospitals use a 11-variant test, while most others check for only four variants.

Different Tests May Be Needed for Different Ancestries

The more variants a test screens for, the better the chance of finding rarer gene forms in ethnically diverse populations. For example, different variants are responsible for the worst deficiencies in people of African and European ancestry, respectively. There are tests that scan for hundreds of variants that might slow metabolism of the drug, but they take longer and cost more.

These are bitter facts for Scott Kapoor, a Toronto-area emergency room physician whose brother, Anil Kapoor, died in February 2023 of 5-FU poisoning.

Anil Kapoor was a well-known urologist and surgeon, an outgoing speaker, researcher, clinician, and irreverent friend whose funeral drew hundreds. His death at age 58, only weeks after he was diagnosed with stage 4 colon cancer, stunned and infuriated his family.

In Ontario, where Kapoor was treated, the health system had just begun testing for four gene variants discovered in studies of mostly European populations. Anil Kapoor and his siblings, the Canadian-born children of Indian immigrants, carry a gene form that’s apparently associated with South Asian ancestry.

Scott Kapoor supports broader testing for the defect — only about half of Toronto’s inhabitants are of European descent — and argues that an antidote to fluoropyrimidine poisoning, approved by the FDA in 2015, should be on hand. However, it works only for a few days after ingestion of the drug and definitive symptoms often take longer to emerge.

Most importantly, he said, patients must be aware of the risk. “You tell them, ‘I am going to give you a drug with a 1 in 1,000 chance of killing you. You can take this test. Most patients would be, ‘I want to get that test and I’ll pay for it,’ or they’d just say, ‘Cut the dose in half.’”

Alan Venook, the University of California-San Francisco oncologist who co-chairs the panel that sets guidelines for colorectal cancers at the National Comprehensive Cancer Network, has led resistance to mandatory testing because the answers provided by the test, in his view, are often murky and could lead to undertreatment.

“If one patient is not cured, then you giveth and you taketh away,” he said. “Maybe you took it away by not giving adequate treatment.”

Instead of testing and potentially cutting a first dose of curative therapy, “I err on the latter, acknowledging they will get sick,” he said. About 25 years ago, one of his patients died of 5-FU toxicity and “I regret that dearly,” he said. “But unhelpful information may lead us in the wrong direction.”

In September, seven months after his brother’s death, Kapoor was boarding a cruise ship on the Tyrrhenian Sea near Rome when he happened to meet a woman whose husband, Atlanta municipal judge Gary Markwell, had died the year before after taking a single 5-FU dose at age 77.

“I was like … that’s exactly what happened to my brother.”

Murray senses momentum toward mandatory testing. In 2022, the Oregon Health & Science University paid $1 million to settle a suit after an overdose death.

“What’s going to break that barrier is the lawsuits, and the big institutions like Dana-Farber who are implementing programs and seeing them succeed,” she said. “I think providers are going to feel kind of bullied into a corner. They’re going to continue to hear from families and they are going to have to do something about it.”

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

Subscribe to KFF Health News’ free Morning Briefing.