Background: It Started with Opioids

The drug overdose crisis encapsulates a complex and ever-evolving landscape prompting robust public health responses from different health and community organizations. The toll that overdose deaths are having on society is becoming more apparent each day, reflecting the urgency to properly mitigate this situation.

Daniel Ciccarone, MD, MPH, professor of family and community medicine at the University of California, San Francisco, has termed the “triple wave phenomenon” to best describe this overdose crisis. Throughout different waves over the years, different drugs have been involved with drug overdose mortality:

  • Wave 1 was characteristic of prescription opioids starting in the 1990s.

  • Wave 2 was characterized by the rise of heroin-related deaths in the mid-2000s.

  • Wave 3 has been dominated by illicitly manufactured fentanyl climbing dramatically after 2013.2

  • Wave 4 still includes fentanyl overdoses but has stretched to also include stimulants such as methamphetamine and cocaine, and is underway now.

It’s important not to look at these waves as independent phenomena, but as closely linked together and affected by both supply- and demand-side factors. Herein, we review Wave 4 of overdose deaths and what it means for the healthcare workforce.

Overdose Mortality Involving Fentanyl and Stimulants


The massive increase in illicitly manufactured fentanyl in 2013 has continued to make the street supply very volatile for people who use drugs (PWUD). According to Mattson and colleagues in the MMWR CDC February report, from 2013 to 2019 the age-adjusted rate of deaths involving synthetic opioids other than methadone increased 1040%.3

Merianne Spencer, MPH, and colleagues at the CDC National Center for Health Statistics reported in May that from 2016 to 2021 the age-adjusted overdose death rate involving fentanyl rose by 279% (5.7 per 100,000 in 2016 to 21.6 per 100,000 in 2021).4


Overdose deaths involving stimulants – specifically cocaine and methamphetamine – have been rising dramatically as well and are increasingly involved in overdose deaths concurrently with illicitly manufactured fentanyl. Hoopsick et al examined the multiple cause of death database for deaths involving methamphetamine and co-involvement with heroin or fentanyl from 1999 to 2021. There was shown to be a 50-fold increase in methamphetamine mortality rate, alongside increasing deaths that co-involved heroin or fentanyl.5 From 2013 to 2019, the age adjusted rate of deaths involving psychostimulants increased by 317% and cocaine by 206%.3 Peppin et al discussed the complex nature of overdose deaths, for which most of the time involve multiple substances. For example, the combination of an opioid and a psychostimulant was responsible for over 18% of the drug overdose deaths in 2018.6

There was a three-fold increase for cocaine-related mortality, and a five-fold increase for psychostimulant involved mortality from 2012 to 2018.2

Cano et al looked at CDC data to examine state-level changes in overdose deaths involving psychostimulants excluding cocaine. They found that from years 2015 and 2016 to 2017 and 2018, dramatic increases in psychostimulant-involved overdose mortality rates were seen in 42 of 47 states where data was available.7 As Mansoor et al further pointed out, while psychostimulant involved deaths have been concentrated in the West, there have been massive increases across the country.8

To further highlight the drastic increase in concomitant cocaine and fentanyl use LaRue et al analyzed 1 million urine drug test results from January 2013 to September 2018. They concluded that positivity rates for non-prescribed fentanyl among the cocaine-positive results increased a shocking 1850%, from 0.9% (95% CI, 0.7%-1.1%) in 2013 to 17.6% (95% CI, 16.1%-19.1%) in 2018.9

Drug Seizure Data


The US Customs and Border Protection (CBP) is one of the main entities involved with the detection and interdiction of drugs that enter in the United States through air or land ports of entry or across the southwest border. Pardo et al shed light on this process in their research paper on fentanyl seizures stating that the CBP data for fiscal years 2015 to 2019 showed a rising trend from 32 kg to 322 kg (70.5 lbs to 710 lbs).10 The CBP, from September 2021 to August 2022 seized more than 200,000 pounds of illicit drugs at the border, which included 13,581 pounds of illicit fentanyl and 172,623 pounds of methamphetamine.11

The latest DEA National Drug Threat Assessment (NDTA) report, from 2020, listed seizures of both methamphetamine and cocaine. The DEA seized 53,079 kg of methamphetamine nationwide in 2019, which was a 55% increase from 2018 (34,270 kg).12 Reports of methamphetamine to the NFLIS have increased by 75% since 2014. The NDTA 2020 report also stated that cocaine ranked third overall in the top 25 most frequently identified drugs to the NFLIS.

At the state level, there have been varying reports of cocaine seizure data with fentanyl contamination rates. Additionally, the Office of National Drug Control Policy published the High Intensity Drug Trafficking Areas Program 2022 Report to Congress highlighting several threat assessments for cocaine contamination with fentanyl in the Atlanta-Carolinas, Central Florida, North Florida, South Florida, New York/New Jersey, North Central, Northern California, Ohio, and New England regions.13

In 2021, the Massachusetts Drug Supply Data Stream Boston Report revealed that of 25 submitted cocaine samples 12% contained fentanyl.14 Other included data showed that of 51 counterfeit opioid pills 15.4% also contained fentanyl.14

In New York, police department data revealed that cocaine contamination with fentanyl had risen from 2% in 2017 to 8% in 2021. Michelle Nolan, an epidemiologist at the city health department, stated “cocaine users are more vulnerable to overdosing on fentanyl because they have not built up the same tolerance for opioids as heroin users” further emphasizing the physiologic susceptibilities of cocaine users inadvertently ingesting fentanyl.15

Potential reasons for this variation in contamination could be from cocaine production being predominantly in South America, and the access for importation via the Caribbean route. Lastly, seizure data from the Pennsylvania DEA’s office, from 2015 to 2017, analyzed more THAN 30,000 cocaine samples concluding that less than 1% contained traces of fentanyl. However, a year-to-year analysis revealed a 112% increase in cocaine/fentanyl samples from 63 samples (2016) to 134 samples (2017) highlighting that there was still a relevant increase from prior baseline data.18

From this data, we can elucidate that cocaine contamination rates have been increasing over the past 8 years in accordance with the rise in illicit fentanyl availability. The exact degree of contamination is variable, and dependent on geographical location.
Intentional vs Cross-Contamination

Given this contamination data, we must ask ourselves, how and why this is occurring? Some theorists suggest intentional lacing and unintentional lacing of cocaine with fentanyl. In a 2019 VICE article titled “The Truth About Drug Dealers Lacing Cocaine with Fentanyl,” the authors pointed out that the DEA’s NDTA report stated “most cocaine-fentanyl mixtures are most likely not mixed at the wholesale level and the majority are probably unintentional” thus downgrading the intentional lacing theory.19

On the same article, Dr. Ciccarone expressed a similar opinion, explaining that due to the nature of both products being sold by dealers for an upper and downer effect there is a high chance of cross contamination at the street level.19 This cross-contamination has likely occurred for years with less potent opioids (ie, heroin) not resulting in accidental overdoses. However, with fentanyl replacing heroin, even trace amounts of inadvertent fentanyl powder contamination have a higher risk of toxicity since it is 100 times more potent.20

Primary care is one of the main entry points into the healthcare system, and thus serves as an excellent opportunity for patients with substance use disorder to develop longitudinal relationships with their providers. Providers should perform adequate social history assessments asking what substances patients use (tobacco, alcohol, illicit substances), a temporal relationship with substance use, the route/dose, and if they are interested in pharmacological/nonpharmacological treatment or risk mitigation.

The biggest emphasis in communication with patients should be using nonjudgmental terms, and the importance of patient health and safety. An adequate assessment of the patient’s past medical history for co-existing mental health disease and chronic pain should also be performed. For patients using cocaine in particular, who do not want to use illicit opioids like fentanyl, providers should be educated on the cardiovascular and cerebrovascular risks of using cocaine and harm reduction strategies, including polysubstance use, fentanyl test strips, and naloxone intranasal spray.

Patients need to be counseled on the medical impact of cocaine and how it blocks the uptake of dopamine, serotonin, and norepinephrine, which can ultimately lead to tachycardia and hypertension.21 Vasoconstriction can also lead to more serious acute myocardial infarction and stroke. Repeated cocaine use also increases one’s risk for premature atherosclerosis and heart failure and may have a larger impact in older patients.22 When cocaine is laced with fentanyl, the potentially opioid-naïve user experiences a lethal fentanyl exposure, thus carrying a higher risk for respiratory depression and arrest as compared to using cocaine without an opioid.

Patient counseling about the health effects of cocaine has the potential to reduce use, hospitalization, and mortality. Cessation of cocaine is the ideal and safest strategy in reducing health events, but if a patient continues to use despite known harms, providers should still be aware of counseling points with use. It is important to counsel patients on avoiding mixing cocaine with other drugs, especially alcohol. The combination of cocaine and alcohol has been shown to create a toxic by-product known as cocaethylene. Cocaethylene has a longer half-life (1.68 hours vs 1.07 hours) and smaller elimination rate constant clearance (0.42 vs 0.67 l/h) than cocaine, further increasing risk for cardiovascular and toxic overdose events.23 Quantity control and using with other individuals is also recommended in order to prevent overdose events. It is advisable if one chooses to use cocaine to start with a small amount and go slowly.

As discussed, overdose mortality involving illicit fentanyl and psychostimulants have drastically increased over the years. Thus, the implementation of public health and harm reduction measures are more important than ever. A popular harm reduction measure currently being utilized are fentanyl test strips (FTS). Fentanyl test strips are a form of drug testing technology that can detect the presence of fentanyl in different kinds of drugs (heroin, methamphetamine, cocaine, etc.).24 Fentanyl test strips allow PWUD to be able to figure out what is in the illicit drug supply and the opportunity to reduce their risk of an overdose situation.

It is important for primary care and healthcare providers to be aware of state laws surrounding FTS, where to obtain them, and be willing to provide them to patients who use illicit substances. As of August 2023, the states in which FTS are illegal to possess include Texas, Oklahoma, Kansas, Michigan, Kentucky, Indiana, Iowa, South Dakota, North Dakota, Montana, Idaho, and Utah..25 Most recently, under Senate Bill 164, Florida decriminalized FTS excluding them from the definition of “drug paraphernalia” and instead as a narcotic-testing product.26 Lastly, syringe services programs that work with PWUD can benefit from the utilization of FTS for these aforementioned reasons. The importance of keeping PWUD safe in this unpredictable and volatile street supply is of utmost urgency.

Peiper et al conducted an online survey of people who inject drugs (PWID) about their most recent FTS use in North Carolina. According to the study, 63% of the sample was reported to be a positive FTS result, and 81% reported utilizing FTS prior to consuming their drugs.27 The study also elucidated that 43% reported actual changes in their drug use behavior, and 77% indicated increased perceived overdose safety by using FTS. These findings are of importance because they highlight the beneficial utility that FTS can offer those who use drugs.

Intranasal Naloxone

Given the risk of cross contamination with cocaine and fentanyl, if a provider identifies a patient using illicit stimulants/opioids/hypnotics during screening they should offer and educate on the use of intranasal naloxone to prevent an accidental opioid overdose. Narcan 4 mg, an intranasal opioid antagonist, was recently granted over-the-counter status by the FDA and will be available on most pharmacy shelves by the end of 2023.28 Most states have standing orders at community pharmacies for prescribing Narcan as well, which further increases access and gets this life-saving drug into the hands of the public.

Our country is witnessing an unprecedented surge in psychostimulant-related deaths due to cross contamination of illicitly manufactured fentanyl available at the street level. This surge is now being referred to as the “fourth wave” phenomenon following the current third wave of illicitly manufactured fentanyl. Cocaine, in particular, has been shown to have cross contamination rates varying from state-to state. Exact locations, preferred drug of use, and the level of drug mixing at the street source appear to have an impact on the contamination rates with fentanyl.

As a healthcare professional, it is imperative to be aware of the health risks of patients using cocaine, as well as risk mitigation options including appropriate quantity use, fentanyl test strips, and intranasal naloxone – all of which can reduce or prevent an accidental opioid overdose.


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