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Last year, more Americans died from drug overdoses than we lost in the Vietnam war. Rates of drug overdose deaths have overtaken car accidents to become a leading cause of death among working-age Americans. While some drugs, especially in the opioid class, are quite dangerous by themselves, combing multiple substances drastically increases the chances of death for a variety of reasons. Read on to learn more about some of the potentially deadliest drug combinations and how they put the body in danger.

The Deadliest Drug Combinations to Avoid

Opioids and Fentanyl

Fentanyl is an extremely powerful synthetic opioid that killed Michal Jackson, Prince, Tom Petty, and tens of thousands of other Americans. A sand-sized grain of pure fentanyl can kill a grown man. It is often added to heroin or fraudulent pain pills to increase potency, so users may not actually be aware of the combination until it’s too late. Fentanyl and other opioid drug overdoses can be reversed with a drug called Narcan if given quickly enough. As the opioid epidemic gets worse, legislation is pushing for Narcan to be available not only to first responders, but even to teachers, parents, and drug users themselves.

Cocaine and Heroin – “Speedball”

Combining a powerful stimulant and a depressant is a recipe for heart trouble. A so-called “speedball” has been responsible for the death of many celebrities, including John Belushi and River Phoenix. Part of the problem is that the effects of the cocaine can blunt the depressant power of the heroin (and vise versa) so that the person doesn’t realize they are overdosing or seek help until it’s too late and their body begins to shut down. Although Narcan can reverse the effects of too much heroin, there is no antidote for cocaine, meaning that so-called “supportive care” is the only thing medical professionals can offer for this type of overdose.

Benzodiazepines or Barbiturates and Alcohol

Benzodiazepines work on the same area of the brain as alcohol; the same is true of the older class of tranquilizing drugs known as barbiturates. Barbiturates combined with alcohol killed stars like Judy Garland and Whitney Houston. These days, barbiturates have mostly been abandoned in favour of benzodiazepines like Valium and Xanax, presumably because the latter is safer. When combined with alcohol, the effects of both drugs are greatly magnified.

Because these substances affect the part of the brain responsible for automatic movements like breathing, an overdose can quickly result in unconsciousness followed by respiratory arrest, which will lead to death. Furthermore ,“cross-tolerance” and addiction can occur rapidly with both alcohol and tranquilizers. Once the brain is adapted to having these substances constantly in the body, stopping “cold turkey” can lead to seizures and death. That’s why a benzodiazepine and/or alcohol addict who wants to get clean should ideally go to a medically-supervised detox program.

Antidepressants and Narcotics

Antidepressants change the levels of important neurotransmitters in the brain like serotonin and dopamine. Unfortunately, several kinds of illegal drugs can also affect the levels of these neurotransmitters, and when the two substances are combined, the user can experience dangerous side effects. For example, drugs like ecstasy increase levels of serotonin to the point where a user who is also on an antidepressant may come down with “serotonin syndrome,” a deadly neurological condition that can result in loss of the body’s temperature regulation system followed by death. Furthermore, the strange, seemingly-unrelated symptoms of serotonin syndrome may be missed by medical professionals until it’s too late.

Drugs and Non-Narcotic Substances

Sometimes, narcotics are taken with over-the-counter medications like allergy pills. These seemingly innocuous combinations can actually be quite deadly. Although allergy medications are not narcotic, they can still affect rates of breathing and pulse. Cough syrup also contains up to 10% alcohol. When combined with other drugs that slow respiration (such as heroin), the allergy or cough medicine can lead to cardiac arrest. On the other hand, “daytime” drugs sometimes include ingredients that can increase pulse, which can be dangerous when combined with amphetamines or cocaine.

Additionally, other non-narcotic prescription drugs like those taken for blood pressure can also be dangerous when combined with alcohol or street drugs. Most of these medications will have warnings on the label if combining with depressants like alcohol is considered high-risk, but there’s not always a good way to know. Unfortunately, the stigma around drug use may lead to patients avoiding the issue when speaking with their doctors, even if a knowledge of possible toxic drug combinations could be life-saving.

Gabapentin and Opioids or Benzodiazepines

Gabapentin is an anti-epileptic drug that is also used for nerve pain and off-label for anxiety. As doctors explore alternatives to opioids for pain, gabapentin is being increasingly prescribed, because it’s not technically a narcotic. Although not deadly on its own—it’s practically impossible to overdose on it— gabapentin may have a synergistic effect on “downer” drugs. In Kentucky, a measurable amount of gabapentin has been found in the bloodstream of more than a quarter of 2016 overdose victims. Doctors are still investigating a possible mechanism for this phenomenon.

The Need for Effective Drug Treatment and Rehab

As we have seen with rates of opioid abuse in America, no one is immune to the ravages of drug addiction. There are dozens of toxic drug combinations, and hundreds of people are poisoning themselves every day. Why do people seek these combinations out? The answer is certainly complex, but scientific evidence points to underlying conditions like depression, anxiety, and trauma as being at the root of the majority of substance abuse.

In many rural and underserved areas, an inadequate mental health care system is combined with a dead-end economy and lack of opportunity, especially compared with previous generations. Drug use becomes an appealing way to self-medicate these painful circumstances, and it’s costing so many lives that the average life expectancy for Americans is actually falling for the first time in decades. 

How do we address this crisis? Increased funding for mental health care, jobs programs, more detox and treatment facilities, and other community-level interventions may be the best way to stop people from seeking out these deadly combinations of drugs. The spike in drug overdose deaths has been decades in the making and will require focused and sustained effort if we want to halt the spiral before more Americans die.

If you or loved one is struggling with substance abuse we can help.

We offer a comprehensive outpatient drug rehab program that works to heal the problem from the inside out. By identifying what lies at the root of substance abuse we can begin to heal the source of the problem. Each situation is different which is why we offer highly personalized treatment options that address the unique mental, physical, and emotional health or each client. 

Our outpatient drug rehab Los Angeles, offers a holistic approach to treatment that combines effective evidence-based therapies to address mental and emotional distress. Our functional nutrition program addresses biochemical imbalances linked to substance abuse and a number of other co-occurring mental health disorders.

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Written By: Linda Whiteside


Licensed Clinical Professional Counselor who has been providing mental health services for over 10 years.

Medically reviewed by: Dr. Ryan Peterson


Went to medical school at The George Washington University School of Medicine in Washington, D.C.

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