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The Millennium Health Signals Report is a periodic publication by Millennium Health, a diagnostic laboratory specializing in drug testing. To decrease yearly deaths, the report analyzes trends in substance use across the U.S. based on millions of urine drug test results from healthcare settings, including addiction treatment centers and pain management clinics.
On February 11th, 2025, the agency released a new report, titled, “Millennium Health Signals Report – Shifting Tides: The Continued Evolution of the 'Fourth Wave' of America’s Overdose Crisis.”
This article explains the report's findings, including the most common cause of death in drug users during this "fourth wave" of the current opioid epidemic in the United States.
The latest in the fourth wave of the opioid epidemic
The opioid crisis started in the late 1990s (the "first wave"), as a result of the overprescription of opioids under false claims that these drugs were not addictive. In 2010-2013, when law enforcement made it harder to procure opioids, many users turned to heroin (the "second wave").
From 2013 forward, illicitly manufactured fentanyl (50 times more potent than heroin) flooded the drug supply, mostly from Mexico and China, skyrocketing deaths by overdose (the "third wave"). The pandemic saw an increase in drug misuse and addiction. Since 2019, mixing fentanyl with stimulants, such as meth or cocaine, or sedatives such as benzodiazepines has characterized the fourth wave of the opioid epidemic. [1]
Many people don’t know they’re mixing fentanyl with other drugs. Nearly 90% of fentanyl-positive drug tests also contain other substances—a deadly combination that can lead to overdose and may complicate treatment. For example, alcohol and many of the drugs detected with fentanyl enhance the respiratory depressant effects of opioids, increasing the risk of overdose and other health complications.[2]
According to the 2025 Millenium report, drug overdose mortality rates in the U.S. decreased by nearly 17% during the 12-month period that ended in July 2024. This trend was justified by a decrease in deaths by fentanyl alone. The decrease in fentanyl-related deaths was likely due to harm reduction tools, including the overdose reversal agent naloxone, increased access to telehealth, availability of drug checking kits like fentanyl test strips, and diminished purity of the drug in combination with increased tolerance in users. [3][4][5][6]
Use of cocaine, meth, and heroin with fentanyl increased
Despite this encouraging trend, the involvement of stimulants in fentanyl-related deaths is increasing. Nine out of ten urine samples containing fentanyl were also positive for other substances, with nearly half containing three or more.
Methamphetamine was the most common drug detected with fentanyl in 2024, followed by cannabis, parafluorofentanyl, cocaine, and acetylfentanyl. From 2018 to mid-2023, the DEA tested 500 samples positive for fentanyl from individuals deceased from drug overdose and found only fentanyl in just two of the samples. [7]
Consistent with this trend, 62% of the population who used fentanyl in 2024 also tested positive for methamphetamine (a 14% increase from 2023), and more than 27% tested positive for cocaine (a 14% increase from 2023).
Heroin use with fentanyl also saw a dramatic 18% surge from 2023 to 2024, mostly in the latter part of 2024 (the first increase since 2016, possibly reflecting changes in chain supply). Over 23% of the population using fentanyl was also positive for heroin in 2024.
Fentanyl polysubstance use by region
The report also highlighted regional differences in fentanyl co-use, with methamphetamine being more common in the West (70% of co-use), cocaine in the Northeast (54% of co-use), and heroin in the Midwest and South (though an increase in heroin co-use was evident across the country).
Carfentanil is a lethal fentanyl analogue used in veterinary medicine for anesthesia in large animals. Carfentanil is 100 times more potent than fentanyl, and its use has recently made a comeback across the U.S., most prevalent in the Northeast. In contrast, cannabis use was comparable across all regions. [8][9][10]
Stimulant and fentanyl polysubstance use
The combination of stimulants like cocaine or methamphetamine with fentanyl is extremely dangerous and, unbeknownst to users, increasingly common in illicit drug markets.
Stimulants speed up the nervous system while fentanyl slows it down, creating a deadly push-and-pull effect on the body.
This mix increases the risk of overdose, heart failure, and respiratory distress, often catching users off guard. A single relapse can be far more lethal than it was in the past.
Heroin and fentanyl
While heroin is already highly addictive and deadly, fentanyl is 50 to 100 times more potent than heroin, drastically increasing the risk of overdose. Many users don’t realize their heroin is laced with fentanyl, leading to unexpectedly fatal doses, even for those with a high tolerance. For recovering addicts, this means that relapsing is much more dangerous than it was in the past.
Other important findings
Despite an encouraging trend showing a decrease in overall overdose deaths, and despite a historic low (at 6%) in the detection of prescription opioids in people positive for fentanyl, over 100,000 Americans still died in the year covered by the report. [3][11]
Opioids continue to be the most fatal drug in the United States, with manufactured fentanyl causing 70% of opioid-related deaths (about 200 per day). Also, overdose rates are increasing in some regions, like the West, and in specific populations, such as Black people, American Indian people, and Alaska Native people. [11][13]
Interestingly, in 2024, the DEA reported a decrease in seized counterfeit pills that contain potentially lethal amounts of fentanyl (≥ 2 mg). However, one or two fentanyl pills could still be lethal.
Conclusion
Fentanyl deaths are dropping, but the risk is still high. Mixing drugs (even unknowingly) is the biggest killer today, and one use could be fatal.
Stay alive. Stay informed. Stay connected.
Need support? Call the SAMHSA Helpline (1-800-662-HELP) for free, confidential assistance.
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