Over the past 20 years the opioid epidemic has washed over the country in waves. First came the arrival of OxyContin and the rapid spread of prescribed opioids in the late 1990s. Then came the migration from prescription pills to injected heroin. And finally, about five years ago, came fentanyl and a staggering rise in overdose deaths.

Each of these three overlapping waves was closely tied to a different form of opioid. Now, addiction experts talk of a cresting fourth wave in the epidemic: the widespread use of stimulants and other illicit drugs alongside opioids.

While combining opioids with other drugs is hardly new — people have been injecting mixtures of heroin and cocaine for more than a century — clinicians and researchers describe a worrisome increase in the number of people who are routinely supplementing opioids with drugs including methamphetamine, cocaine, and benzodiazepines.

This rise in polysubstance use (as it's known in the literature) is scary for several reasons. Although effective medications for opioid use disorder (OUD) exist, the lack of comparable treatments for stimulant addiction complicates the path to recovery for those using multiple substances. Combining opioids with other drugs also increases the risk of overdose, and it can change the physiology of overdoses in ways that may lower the effectiveness of the antidote naloxone.

Outrunning this wave of the epidemic will require a better understanding of the patterns and nuances of polysubstance use, tailored treatment approaches, and a redoubled focus on addressing underlying risk factors for addiction such as homelessness and mental illness, experts say.

"To get ahead of the wave, we have to deal with social issues and the social determinants of health," says Joshua Barocas, MD, an infectious diseases physician at Boston Medical Center (BMC) who specializes in the health complications stemming from addiction. "But at this point we're behind, and it's not for lack of trying."

A troubling new substance-use norm

The Centers for Disease Control and Prevention (CDC) recently highlighted what it calls a growing polysubstance landscape and specifically called out the combination of opioids and stimulants as a serious concern. In a nationwide analysis, the CDC reported that the rate of overdose deaths involving stimulants is poised to increase for the third straight year. The majority of those deaths also involved an opioid — a finding that echoed several previous local studies.

In a new analysis of overdose deaths and toxicology data in Massachusetts, Barocas and his colleagues from the Grayken Center for Addiction at BMC and the Boston University School of Medicine found that polysubstance use was the norm, not the exception. Just 17% of the more than 2,200 opioid-related deaths covered in the study were attributable to opioids alone. Of the remaining deaths, 36% included the presence of a stimulant and 46% included a nonstimulant drug (such as benzodiazepines) in addition to opioids.

Notably, the study is among the first to examine a wide range of social and demographic factors associated with polysubstance overdose deaths. City dwellers, non-Hispanic blacks, people with a mental health diagnosis, and people with recent homelessness were all more likely to have died with opioids and stimulants in their system than with opioids alone, the study found.

Untangling and explaining these associations is a tall task due to the number of variables involved, Barocas says. Local differences in the illicit drug supply, varying substance-use norms across communities, and the specific stresses that accompany homelessness or mental illness may all be part of the picture.

City dwellers, non-Hispanic blacks, people with a mental health diagnosis, and people with recent homelessness were all more likely to have died with opioids and stimulants in their system than with opioids alone.

Jessie Gaeta, MD, the medical director of the Boston Health Care for the Homeless Program, says that many of the homeless patients she sees who have severe OUD have habitually layered opioids with up to four sedatives — benzodiazepines, gabapentin, clonidine, and promethazine — in order to "check out of the toxic environment around them."

But now methamphetamine is increasingly being added to this cocktail, which Gaeta first described in a 2016 piece for Health Affairs. "Methamphetamines have arrived on the scene locally, in droves," she says. "I'm not saying it wasn't here before, but we'd rarely see it on toxicology screens or hear people telling us about it. But now it's almost the norm."

The problem with polysubstance use

Layering multiple drugs makes overdoses far more unpredictable, Gaeta says. A classic opioid overdose, she explains, is characterized by slow, shallow breathing and sedation — effects that can often be reversed by naloxone if help arrives before the heart stops. With other substances in the mix, however, depressed breathing is accompanied and sometimes preceded by dangerous drops in heart rate and blood pressure.

"The clinical overdose syndromes we're seeing are way more complex than typical opioid overdoses, and when we ask people why, and they tell us about what they're using, it's kind of shocking," she says.

The complexity of polysubstance use makes a one-size-fits-all solution all but impossible. Instead, providers must look beyond the available tools and develop tailored treatment programs, especially for populations that have historically been marginalized by the healthcare system, Barocas and his coauthors say.

For instance, medications for OUD such as buprenorphine — which will continue to play a critical role in harm reduction for anybody with OUD, Barocas stresses — may not be enough to stabilize people with multiple substance use disorders.

"We need to rapidly evolve the field of addiction treatment," Gaeta says. Treating OUD, she adds, "doesn't necessarily mean that the stimulant, benzodiazepine, and alcohol use disorders also go away. And it's sometimes a struggle to manage these other distinct addictions."

Evolving a new approach to treating substance use disorder

Given the limitations of available treatments, responding to the rise in polysubstance use will also require a focus on broader social forces, including the drug supply itself, Barocas says.

Much of the polysubstance use described in the recent literature is likely unintentional, stemming not from a desire to achieve a certain effect but rather from drug dealers insinuating fentanyl and other highly potent synthetic opioids into cocaine and other drugs, potentially in an effort to hook new users. Similarly, anecdotal reports suggest that dealers are beginning to cut heroin with methamphetamine.

The ever-evolving drug supply underscores the need for faster data that will provide a more accurate picture of trends in the street. Due to lags in collection and reporting, much of the data available to researchers and clinicians is months if not years old. The overdose deaths in Barocas' paper date back to 2015, for instance, and the CDC data stops in 2018.

New techniques for real-time monitoring of the drug supply, such as fentanyl test strips, are now in circulation and may help providers catch up. But data alone isn't enough, Barocas says. Providers and policymakers must also address the many social determinants of health that are contributing to the wave — housing and homelessness, but also the barriers that prevent people from accessing treatment for addiction and mental health issues.

"Knowing what people are being exposed to and what people are dying from is just the tip of the iceberg," Barocas says. "We have to ask hard questions that we don't have answers to. How do you house unhoused people? How do you maintain services for mental health care? These are larger social issues."