The overdose epidemic in the United States has continued to evolve, shifting in nature and severity over the past two decades. Historically, this crisis has been described in three distinct “waves” — the first driven by prescription opioids, the second by heroin, and the third by fentanyl. Now, a new “fourth wave” has emerged, marking a fentanyl and stimulant overdose crisis driven by the deadly combination of fentanyl with stimulants such as methamphetamine and cocaine. This disturbing trend, identified in a new report from Millennium Health, is quickly redefining how we understand and address substance use in America.
A New Phase in the Overdose Epidemic
Millennium Health, a San Diego-based drug testing laboratory and one of the largest in the country, released data highlighting a dramatic shift in overdose patterns. According to the report, stimulants are now a key driver of overdose-related deaths alongside fentanyl. This shift signals the beginning of the fentanyl and stimulant overdose crisis, a phase where polysubstance use is not the exception, but the norm.
In 2010, stimulants were involved in less than 1% of fentanyl-related overdose deaths. By 2021, that number had surged to nearly one-third, illustrating the rapid and alarming growth of this fourth wave.
The Power of Urine Drug Testing Surveillance
To arrive at these findings, Millennium Health analyzed extensive urine drug test (UDT) data, offering a near real-time look into substance use patterns. UDT data is incredibly valuable because it updates frequently and closely mirrors national, state, and even county-level overdose mortality trends.
The results were sobering: more than 90% of fentanyl-positive specimens also contained at least one other substance, with almost 60% testing positive for between two and four additional drugs. This data underscores the complexity of the fentanyl and stimulant overdose crisis and the need for clinicians to understand the full scope of substances being consumed.
Why Polysubstance Use Is So Dangerous
Polysubstance use increases overdose risk dramatically, especially when users are unaware of the substances they are ingesting. For example, someone may think they are using only cocaine but are unknowingly exposed to fentanyl. This kind of accidental use leaves clinicians in a precarious position, as they may not be prepared to address opioid withdrawal or overdose without accurate information.
Eric Dawson, VP of Clinical Affairs at Millennium Health, emphasized this risk, noting:
“It is tough to organize a battle if we don’t know exactly what we are fighting against… Not knowing what drugs a patient has taken can have potentially deadly consequences.”
Without knowing that a patient has consumed fentanyl, a clinician might not prescribe naloxone or counsel the patient on overdose risks — an oversight that could prove fatal.
Methamphetamine: Fentanyl’s Most Common Companion
Of all the substances detected alongside fentanyl, methamphetamine was the most prevalent, found in 60% of positive specimens. Other common co-occurring substances included cannabis, cocaine, acetylfentanyl, parafluorofentanyl, heroin, prescription benzodiazepines, and the veterinary tranquilizer xylazine.
Since 2015, the co-use of methamphetamine and fentanyl has increased by a staggering 875%, a figure that speaks volumes about the depth of the fentanyl and stimulant overdose crisis. Meanwhile, the presence of prescription opioids and heroin in combination with fentanyl has sharply declined — down 89% since 2013 — reaching historic lows in 2023.
Why Are Stimulants Gaining Ground?
Several factors are fueling this transition from opioids to stimulants. First, methamphetamine and cocaine enhance the euphoric effects of fentanyl. Meth in particular can counteract fentanyl’s sedative effects, known as the “fentanyl nod,” helping individuals stay awake and function.
Second, high-purity methamphetamine is widely available and inexpensive, making it an easy choice for users seeking to modify or amplify the fentanyl experience.
Unfortunately, while opioid use disorder (OUD) can be treated with medications such as buprenorphine, methadone, and naltrexone, there are currently no FDA-approved medications to treat methamphetamine use disorder. This leaves a significant gap in clinical tools and complicates treatment strategies for individuals dealing with both opioid and stimulant use disorders.
Clinical and Public Health Implications
The fentanyl and stimulant overdose crisis presents serious challenges for healthcare providers, addiction specialists, and policymakers. It requires a paradigm shift in how we understand substance use and overdose prevention. Treatment protocols must evolve to account for co-occurring use of opioids and stimulants, and clinicians must be supported with resources and data that reflect this reality.
Dawson stressed that while methamphetamine use is surging, fentanyl remains at the heart of the epidemic:
“This country lost over 110,000 people last year to drug overdose and the majority (80,000 or more) were fentanyl-related; fentanyl must remain our primary focus… However, now a growing number of deaths are being attributed to fentanyl with stimulants and thus we need to ensure solutions are aimed at both.”
What Needs to Happen Next?
Addressing the fentanyl and stimulant overdose crisis demands a multipronged approach:
- Wider access to drug testing and harm reduction tools, including fentanyl test strips and naloxone distribution.
- Improved surveillance and data-sharing from labs like Millennium Health to keep clinicians and communities informed in real time.
- Expanded research and funding for stimulant use disorder treatment options.
- Integrated care models that consider both opioid and stimulant use, especially in underserved populations.
Final Thoughts
The fentanyl and stimulant overdose crisis marks a dangerous new chapter in America’s ongoing struggle with substance use. It is not simply about opioids anymore — it’s about the increasingly complex and deadly combinations of substances that people are using. Understanding this fourth wave is not only a medical necessity but a public health imperative.
As we continue to lose tens of thousands of lives each year, it’s clear that our response must be equally dynamic, informed, and adaptive. The fentanyl and stimulant overdose crisis is here — and it’s demanding our full attention.
