Polysubstance Abuse: Causes, Dangers, and the Best Treatment

Polysubstance abuse refers to a situation in which a person uses multiple drugs or substances simultaneously or in close succession. This dangerous practice has become increasingly common, particularly among people struggling with opioid dependence. 

To help you get familiar with the phenomenon of polysubstance abuse, we created this comprehensive guide that contains vital information about it. With its help, you’ll learn why it happens and what the most common drug combinations are.

Why People Abuse Multiple Substances

People most commonly use multiple substances in a desperate attempt to manage overwhelming circumstances, unbearable pain, or various symptoms. 

More specifically, the primary reasons people turn to this option are:

• Self-medication for untreated conditions. Many individuals use different drugs to cope with chronic pain, trauma, depression, or anxiety when proper medical care isn’t accessible.
• Tolerance development. As the body adapts to one substance, people often add other ones to achieve the same relief or euphoric effects.
• Counteracting unwanted side effects. Some individuals might use stimulants to combat opioid-induced sedation or depressants to ease stimulant-related anxiety.
• Social and environmental pressures. Peer influence, availability of multiple substances, or living in high-stress environments can drive multiple-substance abuse.

What’s particularly troubling is how quickly this behavior can spiral. Someone who starts by occasionally mixing their prescription pain medication with alcohol to sleep better might find themselves dependent on both substances within weeks. The brain doesn’t distinguish between “acceptable” and “unacceptable” combinations; it just adapts to what it receives.

6 Common Drug Combinations in Polysubstance Abuse

While virtually any substances can be combined, certain combinations appear more frequently among users. These pairings are especially dangerous because they often amplify each other’s effects unpredictably.

Let’s examine them in more detail:

#1. Opioids + Benzodiazepines

This combination represents one of the deadliest forms of opioid polydrug abuse. Both opioids and benzodiazepines depress the central nervous system, and when used together, they dramatically increase the risk of respiratory failure. The euphoric effects are also intensified, making this combination particularly addictive.

Due to this, such a combination is rarely prescribed by medical professionals, but it still happens in certain severe cases (for example, for strong pain with anxiety or spasms). In such situations, doctors typically prescribe low doses and continuously monitor the patient.

#2. Opioids + Alcohol

Alcohol and opioids share similar pathways in the brain, both depressing respiratory and cardiac function. This combination is incredibly common because alcohol is legal and readily available, so people use it to enhance opioid effects or cope when their usual opioid supply runs low.

The danger lies in alcohol’s unpredictable interaction with opioids. Even small amounts of alcohol can potentiate opioid effects, leading to accidental overdoses. Many fatal opioid overdoses involve people who thought they were being “careful” by using less of their usual opioid dose, not accounting for alcohol’s amplifying effects.

#3. Alcohol + Any Other Substance

Mixing drugs and alcohol deserves special mention because it’s the most common combination in polysubstance abuse cases. As mentioned above, the legal status and social acceptance of alcohol make it an easy addition to any drug regimen, but it interacts dangerously with virtually every other substance.

Whether combined with prescription medications, illegal drugs, or even other legal substances, alcohol typically amplifies depressant effects and impairs judgment about safe dosing. It also affects how the liver processes other substances, leading to unpredictable drug levels in the bloodstream.

#4. Stimulants + Depressants (Speedballing)

Combining stimulants like cocaine with depressants like heroin, known as “speedballing“, creates a false sense of balance. Users believe the stimulant will prevent overdose from the depressant, while the depressant will ease the stimulant’s harsh comedown.

Needless to say, this is dangerously misguided thinking. The stimulant can mask overdose symptoms from the depressant, and when the shorter-acting stimulant wears off, the person is left with potentially lethal levels of the depressant in their system. Additionally, this combination puts an enormous strain on the cardiovascular system.

#5. Opioids + Cannabis

While cannabis is often viewed as “harmless,” its combination with opioids presents unique risks. Cannabis can enhance opioid-induced sedation and respiratory depression, particularly in people who don’t regularly use marijuana. Some users also employ cannabis to stretch their opioid supply or manage withdrawal symptoms.

People who use both tend to use higher doses of opioids and have more difficulty with treatment adherence. Additionally, the interaction between these substances can also complicate withdrawal, as both can affect sleep, appetite, and mood regulation. The overall impact of this combination likely depends on the dosage, frequency, and individual patient factors.

#6. Prescription Drugs + OTC Medications

This combination often flies under the radar because people assume over-the-counter medications are safe. However, mixing prescription opioids with OTC drugs like antihistamines, sleep aids, or even certain cough medicines (such as the ones containing codeine) can be dangerous.

Many OTC medications contain ingredients that enhance sedative effects or interact with opioid metabolism. For instance, some people use large doses of loperamide (which is also an opioid, although not the one that causes ‘high’) to self-treat opioid withdrawal, not realizing this can cause life-threatening heart rhythm abnormalities.

Signs and Symptoms of Polysubstance Abuse

Recognizing polysubstance abuse can be challenging because symptoms often overlap and mask each other. Some people might appear functional while actually struggling with a complex pattern of substance use that’s slowly destroying their health and relationships.

Still, there are some signs and symptoms that imply such an issue, including the following:

Physical Signs

The physical manifestations of overlapping drug use are often contradictory and confusing, and they may include:

• Alternating between extreme sedation and hyperalertness
• Unpredictable changes in appetite and sleep patterns
• Dilated pupils followed by constricted pupils within hours
• Frequent nausea, vomiting, or gastrointestinal issues
• Unexplained injuries or accidents
• Rapid weight fluctuations
• Poor coordination and balance problems
• Slurred speech that comes and goes

Behavioral Changes

Behavioral symptoms often reflect the chaos of managing multiple substance dependencies. Here are some examples:

• Increasing secrecy about activities and whereabouts
• Multiple prescriptions from different doctors
• Frequent “emergencies” requiring immediate attention or money
• Abandoning responsibilities at work, school, or home
• Defensive or aggressive reactions when questioned about substance use
• Social isolation or dramatic changes in friend groups
• Risky behaviors (e.g., driving under the influence)

Psychological Symptoms

The psychological impact of polysubstance abuse can be devastating and long-lasting. It involves:

• Severe mood swings that seem unrelated to circumstances
• Anxiety, paranoia, or panic attacks
• Depression and suicidal thoughts
• Memory problems and confusion
• Difficulty concentrating or making decisions
• Hallucinations or delusions
• Emotional numbness alternating with extreme emotional reactions

What makes these symptoms particularly concerning is their unpredictability. Someone might seem completely normal one day and be in crisis the next, making it difficult for loved ones to know when intervention is necessary.

5 Common Risks and Dangers of Polysubstance Abuse

The dangers of mixing substances extend far beyond simple addition; they create a multiplicative effect that can be fatal without warning. Let’s see what the most common ones are:

#1. Increased Risk of Overdose and Death

Polysubstance use dramatically increases overdose risk because substances interact in unpredictable ways. A dose that might be safe for one substance becomes lethal when combined with others. 

The timing of substance use also matters critically, as someone might safely use two substances separately but experience a fatal interaction when using them together. This unpredictability makes polysubstance abuse particularly dangerous, even for experienced users.

#2. Complex Withdrawal Symptoms

Withdrawing from multiple substances simultaneously causes immense physical and psychological distress. Each substance has its own withdrawal timeline and symptom profile, and when combined, they can create prolonged and severe withdrawal experiences.

For example, someone dependent on both opioids and benzodiazepines faces the pain and anxiety of opioid withdrawal while also risking potentially life-threatening seizures from benzodiazepine withdrawal. Unfortunately, such complexity often drives people back to substance use just to find relief.

#3. Damage to Organs and Brain Function

Each substance affects different organ systems, and when combined, they create cumulative damage that’s often irreversible. The liver, kidneys, heart, and brain all suffer from the constant chemical assault of multiple substances.

The brain is particularly vulnerable to polysubstance abuse because different drugs affect various neurotransmitter systems simultaneously. This can lead to permanent changes in cognition, memory, and emotional regulation that persist long after substances are discontinued.

#4. Unpredictable Drug Interactions

Unlike single-substance use, where effects are somewhat predictable, polysubstance combinations create unique chemical interactions that can’t be anticipated. Two substances might compete for the same metabolic pathways, causing one to accumulate to toxic levels while the other becomes ineffective.

These interactions can also change based on factors like food intake, hydration status, or even the order in which substances are consumed. This unpredictability makes every use potentially life-threatening.

#5. Higher Rates of Relapse

People struggling with polysubstance abuse face significantly higher relapse rates than those dependent on single substances. This occurs because treating multiple dependencies simultaneously is more complex, and the underlying issues driving polysubstance use are often more severe.

Additionally, many opioid addiction treatment programs aren’t equipped to handle the complexity of polysubstance dependence. This leads to incomplete treatment that fails to address all aspects of the problem.

Who Is Most Vulnerable to Polysubstance Abuse?

Anyone can be vulnerable to polysubstance abuse and develop these patterns, but certain populations face elevated risk due to specific circumstances or characteristics. These include:

• People with existing opioid use disorder (OUD). They represent the highest-risk group, as they often turn to other substances to manage withdrawal symptoms, enhance effects, or cope with the chaos of active opioid addiction. 
• Individuals with untreated mental health conditions. These individuals frequently self-medicate with multiple substances, attempting to manage symptoms that proper medical care could address more safely. Depression, anxiety, PTSD, and bipolar disorder significantly increase the risk of polysubstance abuse.
• Those with histories of trauma or abuse. They often struggle with emotional regulation and may use various substances to numb psychological pain. Childhood trauma, in particular, increases the likelihood of developing substance abuse later in life.
• Young adults and adolescents. Young people are prone to unique vulnerabilities due to brain development, peer pressure, and experimentation tendencies. Early exposure to substances dramatically increases the risk of developing polysubstance abuse patterns that persist into adulthood.
• People who leave traditional rehab programs prematurely or with incomplete detox. They often struggle with residual withdrawal symptoms or cravings that drive them to seek relief through multiple substances. Unfortunately, many substance use disorder treatments don’t fully address the neurobiological aspects of dependence, leaving people vulnerable to relapse and escalation.

Treatment for Polysubstance Abuse

Addressing polysubstance abuse requires a tailored approach that considers the specific drugs involved, the person’s physical health, and any underlying mental health conditions. For some people, a combination of medical interventions, counseling, and long-term relapse prevention strategies works best. 

Because the neurological and psychological effects of multiple substances can be complex, especially when dealing with opioids, treatment programs should also address brain health and emotional regulation to reduce the risk of relapse. Early intervention greatly improves recovery outcomes.

Key Takeaways

Polysubstance abuse represents one of the most dangerous forms of substance use disorder, with risks that multiply rather than simply add together. Being familiar with the complex motivations behind it makes a big difference, as it helps you recognize when you or your loved one needs professional intervention.

Let’s reiterate some key points to remember:

• Polysubstance abuse often stems from attempts to self-medicate or manage withdrawal symptoms from primary substances like opioids.
• Common dangerous combinations include opioids with benzodiazepines, alcohol, or stimulants, each creating unique life-threatening risks.
• Risks include dramatically increased overdose potential, complex withdrawals, organ damage, and higher relapse rates compared to single-substance dependencies.