The Zombie Drug

It’s not the zombie apocalypse—not even close—but most people who view users of the sedative xylazine, which is increasingly mixed with fentanyl in the illicit drug supply, say they resemble zombies, with unseeing staring eyes and a stiff, shuffling walk. Although xylazine is not approved for human use, recreational use of the agent, an alpha2 adrenergic agent dubbed “tranq,” has emerged.

More alarmingly, my colleagues in the addiction field are reporting significant increases in overdose deaths involving fentanyl/xylazine, prompting the Office of National Drug Control Policy to declare xylazine an emerging threat. According to a May 2024 public alert, alpha2 adrenergic agents like medetomidine have also entered the recreational opioid drug supply as fentanyl or heroin adulterants.

Most users don’t knowingly take xylazine or medetomidine. Instead, the drug is added to fentanyl by illegal drug manufacturers. University of Florida professor Bruce Goldberger told me, “To the best of my knowledge, users of fentanyl do not seek illicitly manufactured fentanyl with xylazine. Xylazine is ingested unknowingly.” He also notes, “Xylazine test strips are available to test powders for the presence of xylazine.”

However, some people do buy xylazine for abuse, especially in cities like Philadelphia. Pennsylvania (40.3%), New York (36.5%), and Ohio (34.6%) had the highest xylazine positivity rates over the year, and the top 20 states were all situated along or east of the Mississippi River in Fentanyl-Positive urine tests (Millennium Health July 16, 2024 Signals Alert). According to forensic expert John Thompson, M.D., chairman of psychiatry at Tulane, the combined drug is also found in New Orleans. “This xylazine adulteration trend must be publicized and limited before it becomes an even larger problem," he told me. "Imagine that in addition to the greater than 100,000 drug overdose deaths, we now add to that a generation of young people missing fingers, toes, and limbs.” He is referring to the extreme effects of xylazine on the skin.

Dr Thompson noted that xylazine is not a controlled substance under the Controlled Substances Act. However, xylazine causes profound sedation and hypotension and is associated with deep, unhealing wounds characterized by dark, dead tissue—independent of the injection site—putting users at high risk for amputations.

What Is Xylazine?

Xylazine, a depressant, was discovered as an antihypertensive agent in 1962 by Farbenfabriken Bayer in Germany. The drug was used to sedate animals in the late 1960s and is still used in horse and cattle surgeries.

Xylazine causes significant cardiovascular side effects, including bradycardia, hypotension, and respiratory depression. Medetomidine, a related drug, is generally more potent, with longer duration than xylazine.

Philadelphia: Zombie Central

The addition of xylazine gives the fentanyl legs. As fentanyl's effects normally begin to wear off and withdrawal would otherwise begin, xylazine instead is still active, causing sedation. This leads to prolonging the intoxicating effects of the fentanyl. The user may already be in withdrawal but is so sedated from the xylazine that they are not even aware of it. The epicenter of voluntary abuse of xylazine is Kensington Street in Philadelphia, where illegal drugs are openly used. This documentary video illustrates the problem.

Effects of Fentanyl/Xylazine

When individuals use drugs contaminated with xylazine, they seem heavily sedated or unconscious, with droopy eyelids and a vacant gaze. Their movements and speech are slow and uncoordinated, and the person appears in a trance. The drug's effects on the central nervous system may cause poor balance and coordination, making users stagger or stumble. Prolonged use of xylazine-contaminated drugs can result in severe non-healing skin ulcers and infections. Reduced blood flow and poor nutrition may cause skin to appear pale, gray, or discolored. The depressant effects may slow breathing, contributing to lethargy.

Overdose Deaths Involving Xylazine

From 2015 to 2020, deaths linked to xylazine increased nearly 20-fold. The monthly percentage of detected fentanyl-involved deaths with xylazine rose from 2.9% in January 2019 to 10.9% in June 2022, a 276% increase. Although Pennsylvania, and especially Philadelphia, is ground zero, dramatic increases in fentanyl/xylazine overdose are found throughout the U.S.

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Harvard cardiologist Dan Blumenthal, M.D., told me, “Alpha-2 agonists like xylazine are peripheral vasodilators and lower blood pressure. Overdoses of these agents can result in dangerously low blood pressure and heart rate, both of which can compromise end-organ and peripheral perfusion, resulting in harm to the brain, heart, kidneys, and extremities.”

Sometimes naloxone or nalmefene isn’t given to fentanyl/xylazine patients because their symptoms are confusing or patients deny using opioids. Withholding naloxone can be a tragic error. Also, routine toxicological screening is not performed for xylazine, making intoxication with it difficult to detect and manage.

Hypoxic Effects of Xylazine

Xylazine overdose is commonly encountered in combination with fentanyl, but it has also been detected in mixtures containing cocaine, heroin, and other drugs.

The most common side effects in humans include bradycardia, respiratory depression, hypotension, and brain blood flow and oxygen changes.

In a National Institute on Drug Abuse study, xylazine injected with fentanyl induced a rapid brain oxygen decrease, similar to fentanyl alone. However, the response lacked the second hypoxic phase of the oxygen response occurring with fentanyl alone, a sort of “second chance” for reversal. Also, the duration of the oxygen decrease is much longer with the drug mixture than with fentanyl alone. Hence, a major danger of xylazine plus opioid drugs is prolonged extreme lack of oxygen to the brain.

While large decreases in brain oxygen levels could be tolerated if transient, harmful effects accelerate when hypoxia is prolonged; the hypoxic effects produced by fentanyl/xylazine are difficult to reverse and compromise long-term brain health. Since intranasal naloxone is ineffective against xylazine, getting the patient to an EMT or emergency room is critical for respiratory support and even prolonged resuscitation, as xylazine's effects can be long-lasting.

Treatment of Xylazine Overdose

Treatment of xylazine overdose primarily involves treating symptoms and maintaining respiratory function and blood pressure. Recommendations are to give high-dose naloxone and assess for adequate breathing. Administer supplemental oxygen and prepare for intubation as needed. Check heart rate, EKG, blood pressure, sugar, and oxygen saturation. Intravenous fluids, bladder catheterization, and/or mechanical ventilation may become necessary.

Conclusion

Discouragingly, an ambitious study recently reported in the New England Journal of Medicine failed to show that using evidence-based interventions like distributing naloxone and providing access to medication-assisted treatments (MATs) significantly curbed opioid deaths. Why did communities implementing public health strategies not see a statistically significant reduction in opioid overdose deaths? Counterfeit pills and heroin, cocaine, and meth combined with adulterated fentanyl make deaths more likely. Xylazine and medetomidine are growing threats nationwide, especially since most patients have no idea that fentanyl includes an alpha-2 veterinary medicine.

Addiction is a chronic, relapsing, long-term disease, often ending with premature death. Harm reduction is important but not a cure, as more than 20% of all opioid overdose decedents received some form of naloxone. Research, prevention, early identification, intervention, and treatment are all needed.

Fentanyl overdose itself causes respiratory depression, and overdose-related respiratory depression is a neurological emergency that may lead to brain hypoxia, brain cell loss, and, at worst, coma and death. Although all opioid overdoses can induce brain hypoxia, the danger is magnified with fentanyl/xylazine and related drugs. In addition, the hypoxic effects of heroin and fentanyl are significantly changed by recent consumption of alcohol, benzodiazepines, ketamine, medetomidine, or xylazine.