Polysubstance Use and Overdose Risk

You used more than one drug, or you are not sure what was in the pill, and you need to know whether that mix can stop your breathing. Polysubstance use means more than one drug. CDC defines it as two or more drugs taken together, or within a short time, either on purpose or without the person knowing. NIDA's classroom explainer matches that definition: together at the same time, or separately but close together, and it still counts if the mix was accidental. Purpose can mean changing how another drug feels. Accident can mean fentanyl already in the powder or the pill.

CDC's warning is blunt. Mixing drugs is never safe, because the effects can be stronger and less predictable than one drug alone, and they can be deadly. In 2022, nearly half of drug overdose deaths involved multiple drugs.

The risk, and what it means for treatment, is the subject. It is not a way to mix more carefully, and it is not a home detox plan.

If breathing slows or stops, someone will not wake, chest pain starts, a seizure starts, or body temperature shoots up, call 911. For suicidal thoughts rather than an overdose, call or text 988.

On purpose and by accident

Intentional use, in CDC's words, is taking one drug to increase or decrease the effects of another, or to feel the combination. Unintentional use is taking something that was mixed or cut, often with fentanyl, without knowing. Counterfeit pills are one way that happens. CDC says pills bought illegally may contain illegally made fentanyl or other illegal drugs, and that the safer rule is to take only pills that were prescribed for you and came from a pharmacy. Tell a prescriber every medicine you take, including ones from another clinician, so a new prescription is not added on top of a dangerous pair.

CDC says an opioid-involved overdose often includes other opioids or non-opioids. Examples from death records include illegally made fentanyl with cocaine or methamphetamine, and illegally made fentanyl with benzodiazepines, prescription opioids, or heroin. In 2017, 72.7 percent of cocaine-involved overdose deaths also involved an opioid. In 2020, about 40 percent of deaths involving illegally made fentanyl also involved stimulants.

Xylazine belongs here too. The longer page is the xylazine guide. CDC describes it as a tranquilizer not approved for humans, found in the illegal supply and linked to overdose deaths. It is especially dangerous with opioids such as fentanyl. NIDA says overdose-reversal medicines do not reverse xylazine, and that people should still give naloxone when an opioid may be present, because opioids often are.

Why the combination is harder to read

Stimulants, CDC says, can raise heart rate and blood pressure to dangerous levels. Examples include MDMA, cocaine, methamphetamine, and amphetamines. Depressants can slow breathing. Examples include opioids such as heroin, morphine, oxycodone, hydrocodone, and fentanyl, and benzodiazepines. Mixing the two groups does not balance them. CDC says the results are unpredictable and can modify or mask one or both drugs. A person can feel less affected than they are, and then overdose.

Alcohol is a depressant. CDC says drinking while using other drugs raises the risk of overdose and of serious damage to the brain, heart, and other organs. NIDA makes the breathing point specific for one common pair: opioids taken with benzodiazepines, alcohol, or xylazine increase the risk of a life-threatening overdose, because these drugs sedate and suppress breathing. In 2021, nearly 14 percent of overdose deaths involving opioids also involved benzodiazepines. People who use both are at higher risk of an emergency department visit, a drug-related hospital admission, and dying of an overdose. The FDA has boxed warnings on both opioid and benzodiazepine labels about using them together. CDC's 2022 pain guideline tells clinicians to use particular caution when prescribing them concurrently and to ask whether the benefits outweigh the risks.

The awake, overheating, chest-pain emergency is the stimulant overdose guide. Slow or stopped breathing is the opioid and naloxone guide. In a mixed overdose you may see pieces of both, or one may hide the other until the first drug wears off. If you are unsure, get emergency help. Give naloxone if an opioid might be involved. Stay until help arrives. Do not assume a person who is still talking is safe, and do not assume a person who wakes after naloxone is finished with the emergency.

What changes in treatment

SAMHSA uses "concurrent substance use" for people who use more than one substance, and "concurrent substance use disorder" when more than one disorder is diagnosed at the same time. It lists polysubstance use as another name for the same problem. The guide is for adults. It says research on what works for people who use more than one substance is limited, and then it names the stakes.

Compared with a single substance use disorder, SAMHSA says concurrent use is associated with more lifetime suicide attempts, arrests, and incarceration, more financial and legal problems, a higher likelihood of overdose, and more severe medical and psychiatric illness. The effect depends on the pair. Alcohol is involved in about 15 to 20 percent of opioid overdose deaths, in a figure SAMHSA cites. People who use alcohol and marijuana together are more than twice as likely to drive impaired. Those are risk statements, not a score for one person.

The practical consequence is assessment. SAMHSA says diagnosis and treatment have traditionally focused on one substance at a time. Many people who meet criteria for a substance use disorder use or are dependent on more than one. Among people with opioid use disorder, a large share also use stimulants, alcohol, or tobacco. An added substance increases risk and needs its own response. Screening for every substance, not only the one that brought someone through the door, is how a program avoids treating half the problem.

SAMHSA's guide highlights three approaches that have evidence for adults with concurrent use: FDA-approved pharmacotherapy together with counseling; contingency management together with that medication and counseling; and twelve-step facilitation together with that medication and counseling. "FDA-approved" matters. It means the medicine approved for the disorder that has a medicine, such as opioid use disorder or alcohol use disorder. It does not mean a medicine approved to erase every drug at once. Cocaine and methamphetamine still have no FDA-approved medicine, which the cocaine guide explains. Contingency management is a behavioral approach used for stimulants. It is a clinic program, not a reward chart at home.

CDC says clinicians should offer or arrange medication for opioid use disorder, and that detoxification alone, without those medicines, is not recommended because return to use, overdose, and overdose death become more likely. Using more than one substance does not erase that recommendation. A benzodiazepine or alcohol problem changes how withdrawal is managed. It does not mean the opioid medication should be skipped by default. Why alcohol and sedatives are not stopped on a dare is the benzodiazepine guide. The opioid that now shows up in drugs people did not think were opioids is the fentanyl guide.

Do not try to come off everything over a weekend because you know what you took yesterday. Yesterday's amount is not today's strength, especially when the supply is contaminated. A taper, a substitution, or a flush schedule does not belong here.

What to do in the moment

Tell the dispatcher what you think was used, including more than one drug if you know. Give naloxone if an opioid may be involved, and repeat it if breathing does not return, as the opioid guide describes. Naloxone will not restart breathing that stopped because of alcohol or a benzodiazepine alone. Those emergencies still need the ambulance.

SAMHSA's finding of higher lifetime suicide attempts among people who use more than one substance is a reason to take a crisis line seriously, not a prediction.

What the phrase harm reduction means in federal documents, and which supplies a 2026 SAMHSA letter says grants may buy, is the harm reduction guide. Treatment locations are listed on FindTreatment.gov. When you call, name every substance, including alcohol and medicines that were prescribed. A program that can manage withdrawal from the dangerous one, continue medication for opioid use disorder if that disorder is present, and treat the other substances rather than discharging you for them, is the level of care to ask about.

Call or text (800) 653-9376 if you want help finding treatment that can address more than one substance.

Additional Resources

Sources cited on this page:

• CDC: Polysubstance use facts
• CDC: Polysubstance overdose
• NIDA: Understanding polysubstance use
• NIDA: Benzodiazepines and opioids
• NIDA: Xylazine
• SAMHSA: Treating Concurrent Substance Use Among Adults (PEP21-06-02-002)
• CDC: 2022 opioid guideline recommendations
• SAMHSA FindTreatment.gov
• 988 Suicide & Crisis Lifeline

Common Questions