What drug causes the most deaths? Understanding the overdose crisis

October 8, 2025 •

4 min read

According to the Centers for Disease Control and Prevention (CDC), nearly 80,000 of the approximately 105,000 drug overdose deaths in 2023 involved opioids. This stark statistic provides a crucial insight into what drug causes the most deaths in the modern overdose crisis, highlighting synthetic opioids, particularly fentanyl, as the primary driver of this fatality trend.

Quick Summary

The leading cause of drug overdose deaths is synthetic opioids, with illegally manufactured fentanyl being the most significant contributor. Polysubstance use and other drugs like stimulants also play major roles in overall drug mortality.

Key Points

Fentanyl is the leading cause of acute overdose deaths: Illicitly manufactured fentanyl, a synthetic opioid, is the primary driver of the current drug overdose crisis due to its extreme potency and prevalence in the illicit drug supply.
Polysubstance use significantly increases risk: Combining fentanyl with other drugs, including stimulants like cocaine and methamphetamine, is common and elevates the risk of a fatal overdose.
Alcohol is a major contributor to long-term mortality: While not typically an acute overdose threat like fentanyl, alcohol-related chronic diseases like liver disease and certain cancers cause a large number of annual deaths, exceeding opioid and suicide deaths under a broader definition.
High-risk factors for overdose include changing tolerance: A person's risk of overdose is high after a period of abstinence, as their tolerance for the drug has decreased, making them vulnerable to previously-tolerated doses.
Harm reduction measures are critical for prevention: Public health strategies like the distribution of naloxone, access to fentanyl test strips, and expanded substance use treatment are vital for reducing the death toll.

Fentanyl: The Primary Driver of Overdose Fatalities

While the term 'opioids' encompasses many substances, illegally manufactured fentanyl is the most lethal and widespread contributor to overdose deaths in the U.S. today. Fentanyl is a synthetic opioid that is 50 to 100 times more potent than morphine, and a dose as small as two milligrams can be lethal. The danger is compounded by the fact that many users are unaware they are consuming fentanyl, as it is often mixed into other substances like heroin, cocaine, and counterfeit prescription pills.

The alarming rise in synthetic opioid-related deaths over the last decade has fundamentally reshaped the national overdose crisis. Data from the CDC shows that deaths involving synthetic opioids, primarily illicitly manufactured fentanyl, were involved in approximately 69% of all drug overdose deaths in 2023. The crisis has seen a dramatic shift over three waves, starting with prescription opioids, moving to heroin, and culminating in the current fentanyl epidemic.

The Role of Polysubstance Use

The discussion around what drug causes the most deaths is complicated by the prevalence of polysubstance use—the use of more than one drug. Many fatal overdoses involve a combination of substances, where the effects of one drug, such as a stimulant, are unknowingly mixed with a powerful depressant like fentanyl. The CDC reported that in 2023, nearly 70% of stimulant-involved overdose deaths also involved illicitly manufactured fentanyl. This practice significantly increases the risk of a fatal overdose, as combining substances like opioids and stimulants creates an unpredictable and highly dangerous outcome.

Leading Causes of Drug-Related Mortality

While acute overdose deaths are primarily driven by opioids, it is also important to consider long-term drug-related mortality caused by chronic health conditions. This is where a different substance often comes into focus: alcohol. Some studies and public health analyses suggest that when considering deaths from chronic conditions like liver disease and certain cancers, alcohol accounts for a significantly higher number of total fatalities annually than illicit drugs.

Acute Overdose vs. Chronic Disease Mortality

To better understand the full scope of drug-related deaths, it's helpful to distinguish between acute overdose and long-term health consequences. The comparison table below highlights these differing mortality pathways.


Feature	Acute Overdose Deaths	Chronic Disease Mortality
Primary Cause	Fentanyl, other synthetic opioids, heroin	Alcohol, tobacco, long-term stimulant use
Speed of Onset	Rapid (minutes to hours)	Gradual (years of use)
Mechanism of Death	Respiratory depression, heart failure	Liver disease (cirrhosis), cancer, heart disease
Intervention	Naloxone administration, immediate medical care	Treatment programs, cessation support
Statistics Reflect	Drug poisoning deaths in a given year	Attributable deaths over a longer time span
Key Statistic	Illicit fentanyl was involved in nearly 73,000 US overdose deaths in 2023.	Alcohol is linked to over 105,000 deaths annually under a broader definition.

High-Risk Factors and Prevention

Several factors can increase an individual's risk of a fatal overdose. Awareness of these risks is a critical component of prevention.

Common risk factors include:

Changes in tolerance: After a period of sobriety (e.g., following rehab or incarceration), a person's tolerance for a substance decreases. If they resume use at a previous dose, the risk of overdose is extremely high.
Mixing drugs: Combining different substances, especially opioids with other central nervous system depressants like benzodiazepines or alcohol, is very dangerous and significantly increases the risk of overdose.
Uncertain drug supply: The illicit drug market means that the purity and potency of drugs like fentanyl are unknown. Counterfeit pills containing deadly amounts of fentanyl are a major threat.
Chronic health conditions: Conditions like HIV, hepatitis C, and lung or heart disease can increase the risk of a fatal outcome during an overdose.

Prevention strategies include:

Naloxone availability: The medication naloxone can reverse an opioid overdose if administered in time and is a vital tool for harm reduction.
Fentanyl test strips: These can help users check their drugs for the presence of fentanyl, potentially preventing an accidental overdose.
Access to treatment: Expanding access to treatment for substance use disorders is crucial for long-term recovery and saving lives.

Conclusion: Navigating the Complexities of Drug Mortality

Understanding what drug causes the most deaths is not as simple as pointing to a single substance. The statistics show a duality: illegally manufactured fentanyl is the most significant driver of acute overdose deaths, while alcohol is a major cause of chronic, long-term mortality. The complexity of the issue is further highlighted by the frequent involvement of polysubstance use, where multiple drugs interact to increase fatality risk.

While the focus on fentanyl in the media is warranted due to its role in the immediate overdose crisis, a comprehensive public health approach must also address the widespread harm caused by other substances like alcohol and stimulants. Prevention efforts must prioritize harm reduction, expanded treatment access, and education about the dangers of both potent illicit drugs and the long-term effects of legal substances. Ultimately, the question of which drug is deadliest depends on whether one is measuring the immediate threat of overdose or the cumulative effect of chronic substance use.

For more information on preventing overdose, consult resources from the Centers for Disease Control and Prevention (CDC) on Overdose Prevention.

Frequently Asked Questions

Synthetic opioids, primarily illicitly manufactured fentanyl, are responsible for the most drug overdose deaths in the United States. In 2023, nearly 73,000 overdose deaths involved synthetic opioids, accounting for the vast majority of opioid-related fatalities.

Whether alcohol is more deadly depends on the scope of mortality considered. For acute overdose deaths, synthetic opioids are far more lethal. However, when counting deaths from long-term chronic conditions, such as liver disease and heart disease, alcohol accounts for a higher number of annual fatalities than acute overdose deaths from opioids.

Fentanyl is significantly more dangerous because it is 50 to 100 times more potent than morphine. A very small amount—just two milligrams—can be a lethal dose, making it easy to accidentally overdose, especially when it is mixed into other drugs without the user's knowledge.

Polysubstance use is the practice of using more than one drug at the same time. This is risky because the combination of drugs can produce unpredictable and dangerous interactions. For example, mixing stimulants with opioids is a major factor in overdose deaths involving fentanyl.

Yes, naloxone can reverse an opioid overdose, including one caused by fentanyl, if administered quickly. Because of fentanyl's high potency, multiple doses of naloxone may be needed to reverse the overdose.

During a fentanyl overdose, the potent opioid severely depresses the central nervous system, causing breathing to slow down or stop completely. This leads to hypoxia, a lack of oxygen to the brain, which can cause permanent brain damage, coma, and death if not treated immediately.

Individuals with a history of substance use, those with prior overdoses, and people with changes in their tolerance levels are at a higher risk. Certain populations, such as younger adults aged 18 to 45, have seen fentanyl overdose become a leading cause of death.