One of the defining features of the current overdose crisis is that people frequently don’t know what they’re actually taking. Illicitly manufactured fentanyl — the synthetic opioid responsible for the majority of overdose deaths in the United States — is rarely sold in pure form. It’s mixed with other substances at every stage of the supply chain, sometimes to extend profit margins, sometimes to modify the drug’s effects and sometimes simply because of contamination in clandestine production environments.
The result is a drug supply in which a single bag or pill may contain not just fentanyl but a rotating cast of adulterants: other synthetic opioids more potent than fentanyl itself, veterinary sedatives that naloxone can’t reverse, designer benzodiazepines that extend and deepen sedation and common filler compounds. According to the DEA, drug samples containing multiple substances — often four, five or more — are now the norm rather than the exception.
Understanding what fentanyl is commonly cut with matters for anyone whose life intersects with this crisis: people who use drugs, family members, first responders and anyone who has naloxone and needs to understand its limitations. This article covers the most dangerous adulterants first, followed by the more common fillers.
The Most Dangerous Adulterants
Xylazine (“Tranq”)
Xylazine is a veterinary sedative used to tranquilize large animals. It’s not a controlled substance under U.S. federal law, costs as little as $6 to $20 per kilogram from overseas suppliers and has been found in fentanyl seizures in 48 of 50 states. The White House Office of National Drug Control Policy designated fentanyl adulterated with xylazine an emerging drug threat in April 2023.
Xylazine isn’t an opioid. It works through a completely different mechanism — as an alpha-2 adrenergic agonist — which means naloxone has no effect on it. When someone overdoses on a fentanyl-xylazine mixture, naloxone can reverse the opioid component, but the person may remain deeply sedated or in respiratory distress due to the xylazine. Emergency responders who administer naloxone and see no response or only partial recovery may be dealing with xylazine in the drug supply.
Xylazine also causes severe skin wounds in people who inject it. Even injections far from the original site can produce necrotic ulcerations that can progress to the point of requiring amputation. These wounds don’t respond to standard wound care and require specialized treatment. The combination of naloxone resistance and wound complications makes xylazine one of the most clinically serious developments in the current drug supply.
Carfentanil
Carfentanil is a fentanyl analog originally developed to tranquilize elephants and other large wildlife. It’s estimated to be approximately 100 times more potent than fentanyl and 10,000 times more potent than morphine. A quantity invisible to the naked eye — a few micrograms — can be lethal to a person without opioid tolerance.
Carfentanil first appeared widely in the U.S. drug supply around 2016 and was linked to mass overdose events in Ohio and other states. It receded somewhat after the DEA’s 2019 class-wide scheduling of fentanyl-related substances but has reemerged in recent years — drug checking labs tracking street samples reported carfentanil detections from seven states in 2024, including Florida, Wisconsin, New York, Michigan, Washington, California and New Mexico. Because it’s indistinguishable from fentanyl by appearance and present in such small quantities, even fentanyl test strips may miss it. Multiple naloxone doses may be needed to reverse a carfentanil overdose.
Nitazenes
Nitazenes are a class of synthetic opioids developed in the 1950s as potential pain medications that were never approved for medical use. They reemerged in the illicit drug supply beginning around 2019 — partly in response to the DEA’s class-wide scheduling of fentanyl analogs, which incentivized traffickers to shift to unscheduled alternatives. Several nitazene compounds are now Schedule I substances, but the class is large and chemically diverse and new analogs continue to emerge.
The potency of nitazenes varies by compound, but many are significantly more potent than fentanyl. Metonitazene and protonitazene are among the most commonly detected. In Knox County, Tennessee, 12% of overdose deaths in a 2021 analysis involved metonitazene combined with fentanyl. Because nitazenes are opioids, naloxone does reverse their effects — but given their high potency, multiple doses may be required. The challenge is that standard fentanyl test strips don’t detect nitazenes, meaning a person testing their supply for fentanyl and getting a negative result may still be exposed to a more lethal opioid.
Designer Benzodiazepines (“Benzo-Dope”)
Designer benzodiazepines — sometimes called novel benzodiazepines or illicit benzodiazepines — are chemically modified versions of pharmaceutical benzodiazepines like Xanax and Valium that have never been approved for medical use. They include etizolam, bromazolam, clonazolam, flualprazolam and a growing list of newer variants. Bromazolam became the most prevalent designer benzodiazepine detected in the United States in 2023 after the DEA scheduled several competing compounds, and its prevalence continued to rise through 2024.
When benzodiazepines are combined with opioids, the risk of fatal respiratory depression increases dramatically. During January through June 2020, 93% of benzodiazepine-involved overdose deaths also involved opioids. Designer benzodiazepines are particularly dangerous because they’re often long-acting, they aren’t reversed by naloxone and people using fentanyl may not know benzodiazepines are present. The combination produces the deep sedation sometimes described as “benzo-dope” — a prolonged, difficult-to-reverse overdose state that standard opioid reversal protocols aren’t sufficient to manage alone.
Medetomidine (“Rhino Tranq”)
Medetomidine is a veterinary sedative similar to xylazine, used for procedures on cats, dogs and larger animals. It’s been increasing in fentanyl samples since mid-2024, particularly in the northeastern United States, and has been nicknamed “rhino tranq” to distinguish it from xylazine-adulterated fentanyl. Like xylazine, medetomidine isn’t an opioid and isn’t reversed by naloxone. Its effects are deeper and longer-lasting than xylazine in some formulations. It represents an emerging concern that drug checking labs and harm reduction programs are actively monitoring.
Common Fillers and Bulking Agents
Beyond the pharmacologically active adulterants above, illicitly manufactured fentanyl is routinely cut with inert or low-risk substances used to increase volume and extend supply. These are less acutely dangerous but confirm that street fentanyl is virtually never a pure substance.
Caffeine is one of the most consistently detected fillers in drug supply analysis, appearing across fentanyl, heroin and cocaine samples. It’s cheap and widely available and has physical properties that make it easy to mix with powdered drugs. Diphenhydramine (the active ingredient in Benadryl) is also commonly found in fentanyl samples — it has some sedative properties and may be used to bulk up the apparent effect of the drug. Quinine, historically associated with heroin cutting, continues to appear in some samples. Lidocaine and procaine (both local anesthetics) are used to mimic the numbing sensation users associate with drug potency, lending a misleading sense of quality to adulterated product.
Acetaminophen (Tylenol) has been detected in some fentanyl samples, particularly in pressed counterfeit pills. While not acutely dangerous in single doses, it adds no psychoactive effect, and its presence in pressed pills is further evidence that the contents of counterfeit M30s and other fake pharmaceutical tablets bear no reliable relationship to what they’re supposed to contain.
What This Means Practically
The current drug supply isn’t a product anyone is purchasing in full knowledge of its contents. A person buying what they believe to be fentanyl, heroin or a pharmaceutical opioid is likely receiving a mixture of multiple substances — some of which are more dangerous than fentanyl, some of which naloxone can’t reverse, and some of which standard drug tests don’t detect.
Fentanyl test strips are a meaningful harm reduction tool but have important limitations: They detect fentanyl, not the full range of adulterants in any given sample. A negative fentanyl test doesn’t mean a sample is free of carfentanil, nitazenes or xylazine. Drug checking services — programs that analyze samples using laboratory-grade equipment and report findings back to users — provide far more complete information and are expanding in availability through harm reduction organizations in many states.
Naloxone remains essential and saves lives, but first responders and bystanders using it should understand that some overdoses involving xylazine, medetomidine or benzodiazepines will require more than a single dose, won’t fully reverse or will require additional emergency intervention beyond opioid reversal. Giving multiple doses, calling 911 and keeping the person on their side in the recovery position remain the right actions even when naloxone doesn’t appear to be working.
If you or someone you love is struggling with opioid use, fentanyl dependency or the consequences of the current drug supply, the National Rehab Hotline is a free and confidential referral line available 24 hours a day. We can connect you with treatment programs that offer evidence-based care, medication-assisted treatment and support for people at every stage of the recovery process.
