Polysubstance abuse is the use of more than one drug, either at the same time or within a short period. It includes combining illegal drugs, mixing prescription medications with alcohol, or using several substances in rotation. This pattern is extremely common: among overdose deaths involving synthetic opioids in 2016, almost 80% also involved another drug or alcohol. Far from being an edge case, polysubstance use is now the norm in substance-related emergencies.
Why People Use Multiple Substances
Some polysubstance use is intentional. A person might combine a stimulant with a depressant to balance out the effects of each, chase a more intense high, or manage the comedown from one drug with another. Methamphetamine and fentanyl are frequently used together on purpose, for example, a combination sometimes called “goofballs” when injected together.
Other polysubstance use is completely unintentional. The illicit drug supply is increasingly contaminated. A person buying what they believe is a single substance may actually receive a mixture. A sample expected to contain only fentanyl might also include xylazine (a veterinary sedative), lidocaine, and other cutting agents. Counterfeit pills designed to look like prescription medications often contain fentanyl or other unexpected drugs. The percentage of overdose deaths with counterfeit pill evidence more than doubled between mid-2019 and late 2021.
The Most Common Combinations
The drug combinations driving the most harm have shifted over time. In 2012, the most common cluster found in overdose cases was methamphetamine, heroin, and prescription opioids. By 2023, that shifted to methamphetamine, cocaine, and fentanyl, reflecting fentanyl’s takeover of the illicit opioid supply.
Several combinations show up repeatedly in emergency rooms and overdose data:
- Opioids and stimulants: The share of U.S. overdose deaths involving both fentanyl and stimulants surged from 0.6% in 2010 to 32.3% in 2021. Nearly three-quarters of cocaine-involved overdose deaths in 2017 also involved an opioid.
- Opioids and benzodiazepines: Both slow breathing and sedate the brain, making this pairing particularly lethal. Benzodiazepines appeared frequently in synthetic opioid overdose deaths.
- Alcohol and benzodiazepines: Alcohol was involved in over 27% of benzodiazepine-related emergency department visits in 2010 and more than 21% of benzodiazepine-related deaths. Long-term, this combination damages the liver, kidneys, heart, and nervous system.
- Fentanyl and xylazine: Xylazine, an animal tranquilizer never approved for human use, has spread rapidly through the drug supply. The monthly share of fentanyl-involved deaths that also tested positive for xylazine rose 276% between January 2019 and June 2022.
Why Mixing Drugs Is So Dangerous
When two drugs enter the body at once, their combined effect isn’t always just the sum of both. Sometimes the combination produces a synergistic effect, meaning the total impact is greater than what you’d expect from adding the two drugs together. This is why a dose of one substance that a person has survived before can become fatal when paired with something else.
The specific dangers depend on what’s being combined. Mixing two depressants (like opioids with alcohol or benzodiazepines) compounds the slowing of breathing, heart rate, and brain activity. Each drug amplifies the sedation of the other, and the risk of fatal respiratory failure climbs steeply.
Stimulant-opioid combinations create a different kind of danger. Cocaine or methamphetamine forces the heart to work harder, increasing heart rate and blood pressure while constricting blood vessels. Meanwhile, an opioid like fentanyl suppresses breathing and reduces the oxygen supply. The heart is demanding more oxygen at exactly the moment the lungs are delivering less. This mismatch can trigger cardiac events, brain oxygen deprivation, and death. One study found that cocaine significantly decreased overall blood flow to the brain on its own, a problem compounded when fentanyl simultaneously depresses respiration.
Fentanyl combined with xylazine poses a particularly alarming set of risks. Xylazine deepens and prolongs the loss of consciousness and oxygen deprivation caused by fentanyl. It also causes severe drops in blood pressure and dangerously slow heart rate. Chronic xylazine exposure leads to distinctive, severe skin wounds. The drug constricts small blood vessels, starving tissue of blood flow, while its sedative effects keep users immobile for long periods, creating pressure injuries. These wounds can progress to deep tissue death and serious infections.
Why Overdose Rescue Is Harder
Naloxone (sold as Narcan) reverses opioid overdoses by blocking opioids at their receptor sites in the brain. It works quickly and reliably for opioids alone. But naloxone only addresses the opioid portion of a polysubstance overdose. It has no effect on stimulants, benzodiazepines, alcohol, or xylazine.
This creates a confusing situation for bystanders. Someone may administer naloxone, see the person continue to remain unconscious, and assume the naloxone didn’t work. In reality, the naloxone may have restored breathing by reversing the opioid effects, while the other substances are still causing sedation. If regular breathing returns, additional naloxone doses aren’t needed, even if the person stays unconscious. The key sign to watch is whether the person is breathing adequately, not whether they wake up.
In overdoses involving fentanyl and xylazine specifically, patients often show little to no improvement with naloxone. Because xylazine independently suppresses breathing and heart function through a completely different mechanism, these overdoses frequently require oxygen support and other emergency medical interventions that go beyond what naloxone can provide.
How It’s Diagnosed
Despite how common polysubstance use is, the DSM-5-TR (the standard manual used to diagnose mental health and substance use conditions) does not include “polysubstance use disorder” as a separate diagnosis. Instead, clinicians diagnose each substance use disorder individually. Someone using opioids, alcohol, and benzodiazepines problematically would receive three separate diagnoses. This can make treatment planning more complex, since each substance carries its own withdrawal risks and treatment considerations.
Treatment Challenges
Treating polysubstance use is harder than treating a single substance use disorder, and research on how to do it well is limited. Most medication-based treatments were developed for one substance at a time. Medications for opioid use disorder, for instance, have strong evidence behind them, but studies on how well they work when a person is also using stimulants, alcohol, or benzodiazepines are far less developed.
National guidelines from SAMHSA are clear on one point: using other drugs alongside opioids is not a reason to withhold or stop opioid-specific treatment. Even when someone is co-using benzodiazepines (which creates real medical risk when combined with opioid treatment medications), the consensus is that leaving the opioid use disorder untreated is more dangerous than managing the combination under medical supervision. People using multiple substances may simply need more intensive care.
Behavioral approaches like contingency management (which uses tangible rewards for meeting treatment goals) and cognitive behavioral therapy show promise for people using multiple substances, but they face significant barriers to widespread use in clinical settings. Contingency management in particular has strong evidence but is underused due to funding restrictions and logistical challenges in many treatment programs.
Recovery from polysubstance use often takes longer and involves more setbacks than recovery from a single substance. Withdrawal timelines can overlap or interact. Triggers are more numerous since each substance may be tied to different social settings, emotional states, or routines. Treatment typically needs to address not just the substances themselves but the underlying patterns that drive use of multiple drugs, which frequently include trauma, chronic pain, untreated mental health conditions, or some combination of all three.