Polysubstance Use and Overdose: Why Mixing Substances Is So Dangerous

Using multiple substances at once is a recipe for high risk and disastrous consequences. Whether it’s a drink with a prescription or a street drug that has dangerous ingredients a buyer never knew were in there, combining substances amplifies the risks involved.

Using more than one substance at once is called polysubstance use. Unfortunately, it’s now a major puzzle piece in most opioid overdose deaths.

According to the CDC, among synthetic opioid-involved overdose deaths, nearly 80% also involved another drug or alcohol. When that number sinks in as a fact, the truth reveals that deaths are no longer just about a single drug, but dangerous combinations.

August is Overdose Awareness Month, and understanding polysubstance risk is one of the most important things patients, families, and communities can learn. Let’s review the dangers behind polysubstance use and how AppleGate Recovery can help users and their families take the first steps into recovery.

What Polysubstance Use Actually Means

Polysubstance use occurs whether someone intentionally combines multiple substances or unknowingly consumes a drug contaminated with another substance.

A person using what they believe is a single substance may actually be exposed to a combination they never chose, because fentanyl and other synthetic opioids are often mixed into other drugs at the supply level.

Why Combining Substances Multiplies Overdose Risk

Two substances that are each individually manageable at a certain dose can become lethal when combined, even at doses that wouldn’t be dangerous alone.

This happens because many commonly combined substances affect the same core body systems, particularly the central nervous system and respiratory function. When multiple depressants are involved, the combined suppression of breathing and heart rate can overwhelm the body’s ability to compensate. 

Opioids and Benzodiazepines: A High-Risk Combination

How Benzodiazepines Amplify Opioid Respiratory Depression

Opioids and benzodiazepines are both central nervous system depressants, but they work through different receptor systems. When combined, their sedative and respiratory-suppressing effects don’t just add together. They compound each other, significantly increasing the risk of the kind of respiratory depression that causes fatal overdose.

The FDA has issued a boxed warning, its most serious safety warning, specifically about the risks of combining opioids and benzodiazepines. Patients prescribed both medications face substantially elevated overdose risk compared to patients prescribed either medication alone. 

Common Benzodiazepines to Be Aware Of

Benzodiazepines are commonly prescribed for anxiety, insomnia, and seizure disorders. They include medications like: 

Alprazolam
Diazepam
Clonazepam
Lorazepam

Many patients don’t realize that a medication prescribed for anxiety carries serious risk when combined with an opioid, whether that opioid is prescribed or illicit.

If you’re currently taking or considering Suboxone treatment and also use a benzodiazepine, prescribed or otherwise, it’s critical to tell your provider. 

Opioids and Alcohol: A Deadly Overlap

Alcohol is also a central nervous system depressant, and combining it with opioids carries many of the same risks as combining opioids with benzodiazepines. Both substances suppress breathing, and together, their combined effect on respiratory function can be severe even at doses that would be tolerable individually.

This combination is especially dangerous because alcohol is legal, widely available, and often not thought of as a “drug” in the same category as opioids. 

Someone taking a prescription opioid who has a few drinks may not realize they’re engaging in a high-risk combination. 

Opioids and Stimulants: The Rise of Speedballing

Combining opioids with stimulants like cocaine or methamphetamine, sometimes called speedballing, is a growing driver of overdose deaths. The CDC reports that in 2023, nearly 47% of drug overdose deaths in a subset of monitored jurisdictions involved both opioids and stimulants.

This combination works differently than opioid-depressant combinations. Stimulants and opioids pull the body in opposing directions, one speeding up heart rate and the other slowing breathing. That opposing pull can mask the warning signs of overdose. A person may not appear as visibly sedated as they would with an opioid alone, which can delay recognition that an overdose is happening and delay life-saving intervention like naloxone administration.

Fentanyl and Polysubstance Overdose

Illicitly manufactured fentanyl has reshaped the entire landscape of polysubstance overdose. Because fentanyl is far more potent than heroin and inexpensive to produce, it has been increasingly mixed into other drugs, including cocaine, methamphetamine, and counterfeit prescription pills, often without the buyer’s knowledge.

This means many people experiencing a polysubstance overdose never intended to use an opioid at all. They were exposed to one unknowingly, mixed into a substance they thought they understood.

How Suboxone Treatment Addresses Polysubstance Use

Suboxone treatment stabilizes the brain’s opioid receptors, which reduces the cravings and opioid-seeking behavior that put people at risk of exposure to contaminated or unpredictable drug supplies in the first place.

Treatment from AppleGate Recovery also addresses polysubstance use directly through clinical evaluation and ongoing care. Our providers assess for other substance use during intake and treatment planning, which allows them to address risks specific to each patient, including interactions between prescribed medications and other substances. 

Frequently Asked Questions

What is polysubstance use? 

Polysubstance use refers to using more than one substance, whether intentionally combined or unknowingly present in a drug supply, during the same period or occasion.

Why is mixing opioids and benzodiazepines so dangerous? 

Both are central nervous system depressants that suppress breathing. Combined, their effects compound rather than simply add together, significantly raising the risk of fatal respiratory depression. The FDA has issued its strongest safety warning about this specific combination.

Can you overdose on alcohol and opioids even at normal doses? 

Yes. Combining alcohol with opioids can produce dangerous respiratory depression even when each substance is used at a dose that would be considered safe on its own.

Why is fentanyl involved in so many polysubstance overdoses? 

Illicitly manufactured fentanyl is frequently mixed into other drugs, including stimulants and counterfeit pills, because it’s inexpensive and highly potent. 

What should I do if I think someone is experiencing a polysubstance overdose? 

Call 911 immediately. If naloxone is available, administer it, since it can reverse the opioid component of an overdose. Stay with the person until emergency responders arrive.

Where can I get confidential help for polysubstance use? 

The SAMHSA National Helpline is available 24/7 at 1-800-662-HELP (4357) and offers free, confidential support and treatment referrals. AppleGate Recovery’s outpatient clinics also provide evaluation and treatment for patients navigating opioid use alongside other substances.

Avoid the Risks of Polysubstance Use With AppleGate Recovery

Polysubstance use has changed the shape of the overdose crisis, but it hasn’t changed what works. Evidence-based treatment, honest conversations with providers, and access to care remain the most effective tools available. At AppleGate Recovery, we offer programs that help our patients understand the threat behind polysubstance use and give them the tools and treatment necessary to take the next steps towards safer, more stable recovery.

Contact us today to learn more about our recovery programs.