What Do People Overdose On? The Most Common Drugs

Fentanyl is the single drug most frequently found in overdose deaths in the United States, and it has held that position every year since at least 2017. A federal analysis of death certificates from 2017 through 2023 found that the drugs most commonly involved in fatal overdoses included fentanyl, heroin, cocaine, methamphetamine, oxycodone, morphine, methadone, alprazolam, diphenhydramine, and gabapentin, roughly in that order of frequency.¹ But the picture is more complicated than a simple ranked list, because most overdose deaths involve more than one substance, and many of the drugs that kill people are not the ones they thought they were taking.

Fentanyl Dominates the Numbers

Fentanyl appeared on more overdose death certificates than any other drug across all years studied from 2017 to 2023. It was also the most frequent companion drug found alongside nearly every other substance on the list. Among deaths involving xylazine, for instance, fentanyl was present about 99% of the time. Even among oxycodone-involved deaths, fentanyl showed up in roughly half of cases.¹ That makes fentanyl both the leading standalone cause of overdose death and the substance most likely to be present when someone dies from something else.

The reason fentanyl is so lethal relates to how it acts on the body. Like other opioids, it suppresses the brain’s drive to breathe. But fentanyl is extraordinarily potent, active at microgram-level doses, and recent research has identified an additional mechanism beyond its primary action on opioid receptors. In animal studies, high doses of fentanyl blocked certain potassium channels in nerve cells, leading to abnormal muscle rigidity in the chest wall, sometimes called “Wooden Chest Syndrome,” which can make it physically difficult or impossible to ventilate a person even with rescue breathing.² This chest rigidity, combined with respiratory depression, helps explain why fentanyl overdoses can be so rapidly fatal.

Stimulants Are Involved in More Than Half of Overdose Deaths

Cocaine and methamphetamine together account for a staggering share of overdose fatalities, though often in combination with opioids. During January 2021 through June 2024, about 59% of all overdose deaths in the U.S. involved a stimulant of some kind. Methamphetamine appeared in roughly 31% and cocaine in about 30% of those deaths. Critically, most of these were not “pure” stimulant deaths: about 73% of stimulant-involved overdose fatalities also involved an opioid, with nearly 80% of cocaine-related deaths and about 69% of methamphetamine-related deaths co-involving opioids.³ Only about 15% of deaths involved stimulants alone with no opioid present.

Stimulants kill through different pathways than opioids. Cocaine’s acute dangers are largely cardiovascular: it can trigger dangerously high blood pressure, abnormal heart rhythms, and heart attacks through multiple overlapping mechanisms.⁴ Methamphetamine also stresses the heart, but an underappreciated danger is extreme hyperthermia, an uncontrolled rise in body temperature that can occur even without seizures or excessive physical activity. This overheating can break down muscle tissue and damage organs on its own, and in severe cases it may be the primary cause of death.⁵ Research in animal models suggests that methamphetamine-induced brain hyperthermia can cause the blood-brain barrier to break down, leading to swelling that ultimately shuts down vital functions.⁶

Benzodiazepines and Sedatives

Benzodiazepines like alprazolam (Xanax), clonazepam, and diazepam are among the most commonly involved drugs in both intentional and unintentional overdoses. A large study of over 420,000 suicidal drug overdoses found that benzodiazepines were involved in roughly one in five cases.⁷ On their own, benzodiazepines are rarely fatal in overdose; the body can tolerate surprisingly high doses. The real danger emerges when they are combined with opioids, because both drug classes suppress breathing. Patients exposed to both opioids and benzodiazepines were about 20% more likely to experience an opioid-related overdose than those taking opioids alone.⁸

Alprazolam appears by name in the national data on drug overdose deaths, but the counterfeit pill market has muddied the picture. Many “Xanax” tablets sold on the street contain illicit benzodiazepines like bromazolam or flualprazolam rather than actual alprazolam, sometimes in combination with fentanyl.⁹ A person buying what they believe is a prescription sedative may actually be taking a far more dangerous combination.

Over-the-Counter Drugs That Send People to the Hospital

Not every dangerous overdose involves illicit substances or controlled prescriptions. Acetaminophen (the active ingredient in Tylenol and dozens of combination cold and pain products) is the leading cause of drug-induced acute liver failure in many developed countries.¹⁰ Because acetaminophen is in so many different products, people sometimes take overlapping doses without realizing it, and the margin between a therapeutic dose and a liver-damaging one is narrower than most people assume. The damage unfolds over hours to days, and by the time symptoms become obvious, serious liver injury may already be underway.

Diphenhydramine (the ingredient in Benadryl and many over-the-counter sleep aids) is another drug that shows up frequently in overdose data, appearing among the top drugs listed on overdose death certificates alongside prescription medications and street drugs.¹ In large doses, diphenhydramine affects the heart. It can slow electrical conduction through the heart muscle and prolong the interval between heartbeats, creating the risk of dangerous heart rhythm problems.¹¹ This cardiac toxicity stems from the drug’s ability to block sodium channels in the heart, an effect unrelated to its antihistamine properties.¹²

Antidepressants and Intentional Overdose

Among intentional (suicidal) overdoses, antidepressants carry a higher risk of death than many people expect. Opioids had the highest relative risk of completing a suicide by overdose, but antidepressants ranked third, with a risk more than three times the average of other drug classes.⁷ Older tricyclic antidepressants are especially dangerous in overdose because they interfere with the heart’s electrical system. They block sodium channels in cardiac tissue, which slows the electrical impulses that keep the heart beating in rhythm and can trigger fatal arrhythmias.¹³ Additional mechanisms, including disruption of normal repolarization, interference with adrenaline signaling, and blockade of acetylcholine receptors, all compound the cardiac danger.¹⁴

Newer antidepressants like SSRIs are generally much safer in overdose, which is one reason they have largely replaced tricyclics as first-line treatments. But tricyclics are still prescribed for chronic pain and certain other conditions, and they remain readily available in many households.

Polysubstance Use and Why Mixing Is the Real Killer

The pattern that runs through nearly all of these categories is that most fatal overdoses involve more than one drug. The national data on the most frequently involved drugs shows fentanyl appearing alongside virtually every other substance on the list.¹ The stimulant data confirms this: nearly three-quarters of stimulant-involved overdose deaths also involved an opioid.³ Even alcohol, which many people do not think of as a “drug” in the overdose context, significantly increased the risk of completing a suicide by overdose when combined with other substances.⁷

The danger of mixing is not just additive; it can be multiplicative. Adding a benzodiazepine or sedative to an opioid does not just double the respiratory depression, it pushes the body past a tipping point where breathing can stop entirely. Many people who die from “a fentanyl overdose” actually had cocaine, methamphetamine, benzodiazepines, or alcohol on board as well. A ranked list of individual drugs, while useful, understates how much of the crisis is really about combinations.

Xylazine and the Contaminated Supply

Xylazine is a veterinary sedative, not approved for use in humans, that has increasingly been found mixed into the illicit drug supply, particularly alongside fentanyl. The combination, sometimes called “tranq-dope,” creates problems that go beyond what either drug would cause alone. In animal studies, a non-lethal dose of xylazine decreased the lethal dose of fentanyl by roughly 100-fold, a dramatic synergistic interaction.¹⁵

This combination complicates rescue efforts. Naloxone can reverse the opioid effects but does nothing to counteract xylazine’s sedation and respiratory depression. There is currently no approved antidote for xylazine, and no evidence-based treatment recommendations for its toxicity.¹⁶ Beyond the acute overdose risk, co-exposure to fentanyl and xylazine has been linked to severe skin ulcers at and away from injection sites, a distinctive bent-over posture during intoxication, and the chest rigidity described earlier.¹⁷ People using street opioids often have no idea xylazine is present in what they are consuming.

Counterfeit Pills and Hidden Exposures

A growing share of overdose deaths involve counterfeit pills, tablets pressed to look identical to legitimate pharmaceuticals but containing completely different drugs. The most commonly counterfeited pills are made to resemble oxycodone and alprazolam. These fakes frequently contain illicitly manufactured fentanyl, illicit benzodiazepines, or both.⁹ The person swallowing the pill may believe they are taking a known pharmaceutical at a known dose. Instead, they are taking an unknown amount of a far more potent substance.

This is not limited to domestic street markets. An ethnographic study at tourist-oriented pharmacies in Mexico found that about 40% of controlled substance samples purchased were counterfeit. Pills sold as “Adderall” contained methamphetamine in the majority of cases, and pills sold as “oxycodone” contained fentanyl or heroin.¹⁸ The global expansion of counterfeit pills has widened the population at risk well beyond people who traditionally use street drugs. As one analysis described it, many consumers of counterfeit pills believe them to be real pharmaceuticals and would be unlikely to consume those drugs knowingly.¹⁹

Nitazenes and Emerging Synthetic Opioids

Beyond fentanyl, a newer class of synthetic opioids called nitazenes has begun appearing in the illicit drug supply. These compounds are extremely potent, and the illicit supply is increasingly adulterated with them.²⁰ A cohort study of confirmed nitazene exposures documented cases from 2018 through 2025, finding that poisoning typically presented as deep sedation and slowed breathing, with severe cases requiring intubation after cardiac arrest or dangerously low oxygen levels. Vaping was the most common route of exposure, and in about 38% of cases where intent could be determined, the person had specifically sought out the nitazene.²¹

The clinical concern with nitazenes is that some of them may be even harder to reverse with naloxone than fentanyl, because reversal effectiveness depends heavily on how tightly and how long a drug binds to opioid receptors. Opioids with high receptor affinity or slow dissociation are particularly resistant to naloxone.²² This has prompted research into alternative reversal agents like nalmefene, which has a longer duration of action and slower unbinding from opioid receptors, potentially making it more effective against long-acting or high-potency synthetic opioids.²³

Who Overdoses and Where

The demographics and geography of overdose have shifted considerably over the past decade. In Massachusetts, a state with detailed surveillance data, overdose death rates were historically higher in urban areas, but by 2018 and 2019, rural communities had caught up and in some cases exceeded urban rates. The racial and ethnic distribution has changed as well: fatal overdoses involving fentanyl and stimulants rose sharply and simultaneously in the non-Hispanic Black population in 2020 and 2021, with peaks in people in their 40s and 60s. Among Hispanic residents, elevated rates from 2015 to 2021 were driven largely by synthetic opioids.²⁴ Men die of overdose at higher rates than women across most categories, though among suicidal drug overdoses specifically, women make up a slight majority of the attempts.⁷

The pattern of which drugs kill people in which regions has also changed over time. Prescription opioid deaths climbed steadily from the 1990s through the early 2000s, closely tracking the increase in opioid prescribing and sales.²⁵ That wave was followed by a heroin surge and then the current fentanyl-dominated crisis. The stimulant death rate has also been climbing steeply, with rates for psychostimulants (primarily methamphetamine) nearly tripling between 2018 and 2023.³

Children and Accidental Exposures

Overdose in children follows different patterns than in adults. Pediatric exposures are most often accidental: a toddler finds a pill on the floor, gets into a grandparent’s medication, or is inadvertently exposed in a household where drugs are used.²⁶ A multicenter study of young children who accidentally swallowed highly toxic medications found that cardiovascular drugs and opioids were the most frequent agents involved, together accounting for more than 60% of cases. The median age was three years, and nearly half of the children who ingested the most dangerous medications were under one year old.²⁷

The reassuring finding from that study was that outcomes were generally favorable with prompt medical attention: no fatalities occurred and advanced life support was not needed. But the rising presence of fentanyl in homes and communities, including in counterfeit pill form, has made accidental pediatric exposure more dangerous than it was a generation ago. A single pill that an adult might survive could easily contain a lethal dose for a small child.

Naloxone Saves Lives but Has Real Limits

Naloxone (sold under brand names like Narcan) is now widely available over the counter and has saved countless lives by temporarily reversing opioid overdoses. But it is not a universal antidote. Its effectiveness depends on which opioid caused the overdose. Long-acting opioids and those that bind very tightly to receptors can outlast a dose of naloxone, meaning the person slips back into respiratory depression after an initial recovery, a phenomenon called renarcotization.²² This is why emergency guidance always emphasizes calling 911 even after administering naloxone.

Naloxone also does nothing for the non-opioid components of a polysubstance overdose. It will not reverse the effects of xylazine, benzodiazepines, alcohol, methamphetamine, or cocaine. In an era when most overdose deaths involve multiple substances, rescue breathing and calling for professional medical help remain essential even when naloxone is used and appears to work initially. And for the chest wall rigidity that high-dose fentanyl can cause, naloxone alone may not restore normal breathing even if it reverses the opioid receptor effects, because the rigidity operates through a separate mechanism.² Researchers are actively exploring alternatives like nalmefene, which clears the body more slowly and may hold off renarcotization longer, though a more potent and longer-acting antagonist also carries the risk of triggering more severe and prolonged withdrawal.²³

1
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2
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3
Centers for Disease Control and Prevention (CDC) / MMWR. Drug Overdose Deaths Involving Stimulants ― United States, January 2018–June 2024
4
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PubMed. Hyperthermia in psychostimulant overdose
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PubMed Central. Nitazenes: An Old Drug Class Causing New Problems
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