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Combating lethal drug combinations

Fourth Wave of Drug Overdoses

• • • • • • • April 2024 • • • • • • •

Derek Kerr
Dr. Derek Kerr

In recent years, public health and addiction researchers have identified a Fourth Wave of drug overdoses, namely, deaths related to fentanyl in combination with stimulants like methamphetamine and cocaine.

According to the Centers for Disease Control (CDC), the First Wave, starting in 1999, claimed overdoses from prescription pills like Oxycontin. Tighter control of prescription opioids led to the Second Wave - the 2010 shift to heroin overdoses. In 2013, the Third Wave brought soaring deaths from the synthetic opioid fentanyl.

Opioid Deaths

Surely, the overdose crisis couldn’t get any worse. Not so. The old practice of “speedballing”- taking stimulants along with opioids resurfaced. The percentage of US overdose deaths involving fentanyl plus stimulants increased from 0.6% in 2010 to 32.3% in 2021. The sharpest increase started in 2015, marking the onset of the Fourth Wave;

Fourth Wave graph
The Fourth Wave / Source: Friedman & Shover in Addiction; 9/13/23

A Millenial Health report examined 17,000 urine tests among fentanyl users nationwide in 2023. For the first time, stimulants exceeded the presence of heroin and prescription opioids in fentanyl positive samples. Meth was found in 60% of these urine specimens – a 9-fold increase since 2015. The presence of cocaine tripled.

Moreover, 93% of these fentanyl-positive urine tests detected other drugs. Almost 50% of the specimens contained 3 or more drugs. Nowadays, very few people use fentanyl alone. Hence, a stark feature of the Fourth Wave is multi-drug overdoses.

Counterfeit Pill Poisonings

A deadly feature of Third and Fourth Wave overdoses is counterfeit prescription pills.  According to Drug Enforcement Agency (DEA) reports “Fentanyl traffickers use fentanyl powder and pill presses to produce pills that resemble popular prescription opioids, such as oxycodone and hydrocodone, and other popular prescription drugs, such as alprazolam.” (Xanax). Traffickers use dyes to color the pills, and stamps to imprint them with the markers of prescription drugs. More fatal poisonings are now caused by the unwitting purchase of a “Percocet” or a “Xanax” that turns out to be fentanyl.  Counterfeit pills may contain various other drugs.

Last year, the DEA seized 79 million fake pills containing fentanyl. Alarmingly, “DEA laboratory testing currently indicates that 7 out of 10 pills contain a potentially deadly dose of fentanyl.” This year, the agency cracked down on commercial pill press distributors. For example, the DEA fined EBay $59 million for failing to report sales of pill presses and encapsulating machines.

Features of Fourth-Wave Drug Use

  1. Combining meth or cocaine with fentanyl.
  2. Cognitive and behavioral impairment due to chronic stimulant use – especially methamphetamine, which is now more potent and neurotoxic.
  3. Multi-drug overdoses with higher lethality. Adding tranquilizers like xylazine (aka “tranq”) causes profound sedation that isn’t reversed by the opioid blocker naloxone (Narcan).
  4. Smoking drugs now surpasses the injection route, per a CDC report. Smoking reduces blood-borne infections and skin abscesses. It’s still deadly because drugs are rapidly absorbed through the lungs.
  5. Counterfeit pills containing fentanyl.

The devastating effect of drug addiction is evident from the human wreckage on City Streets and in morgues. Yes, it’s a nationwide plague. But SF overdose rates are twice the national average.”

Why the Surge in Multi-Drug Overdoses?

  1. Like other merchants, drug dealers want to enhance their products. Different drugs are mingled to diversify the euphoria.
  2. When fentanyl is in short supply, dealers “cut” their stock with cheaper sedatives and tranquilizers.
  3. Some fentanyl users willfully use multiple drugs. Stimulants reduce the sleepiness or “nodding out” associated with narcotics. Multi-drug combos can intensify the “rush” or prolong the “high.”
  4. Some users will ingest whatever drugs they can get to alleviate their distress.
  5. It’s the latest manifestation of “deaths of despair” and socio-economic stress.

Implications for Treatment

Multi-drug overdoses are hard to reverse because naloxone (Narcan) only reverses the opioid component. It is ineffective against stimulants, tranquilizers, sedatives or alcohol. Even fentanyl overdoses are challenging because the drug is far more potent than heroin. Multiple doses of Narcan are often needed – and may not work in time.

In a 3/4/24 SF Chronicle Open Forum, Robb Layne, a drug program executive, urged switching to nalmefene (Opvee), a longer-acting FDA-approved opioid-reversal agent used successfully in other states. Opvee could save more lives but will cost more than Narcan. To date, there are no drugs to reverse meth or cocaine overdoses.

Treating meth or cocaine addictions remains difficult. Unlike methadone or buprenorphine (Suboxone), which are safe substitutes for fentanyl and heroin, there are no comparable medications for stimulant use disorders. Effective treatments involve motivational behavioral therapies, notably “contingency management” – rewarding drug users for staying clean. These are labor-intensive treatments and require large, ongoing investments. Worse, meth-induced cognitive impairments hinder engagement in therapy.

San Francisco’s Overdose Crisis

The devastating effect of drug addiction is evident from the human wreckage on City Streets and in morgues. Yes, it’s a nationwide plague. But SF overdose rates are twice the national average. The SF Medical Examiner’s tally of overdose deaths still exceeds two per day.  

According to Medical Examiner data for 2023, of 813 fatal overdoses 657 (81%) involved fentanyl. But meth was detected in 51% of the cases while cocaine appeared in 46%. The presence of heroin and prescription drugs was negligible. Heroin was found in just 4.8% of blood samples. But, the animal tranquilizer, xylazine (aka “tranq”), appeared in 4.4% of samples – more than doubling since 2022.

A glaring disparity in this data is that 82.5% of fatal overdoses befell men. Black men, in particular, were disproportionately affected, as well as homeless men. Surprisingly, 63% of drug deaths occurred in persons aged 45 years and older!  It’s a plague afflicting middle-aged men.

City Strategies Can’t Keep Up

In 2019, City officials convened a Methamphetamine Task Force to address the rise in meth-related overdoses and make “recommendations on harm reduction strategies to decrease and manage methamphetamine use.” Its Final Report called for more of the usual services, plus an innovative Meth Sobering Center with harm-reduction services. Like other health-related reports, it was all carrot and no stick.

In 2022 the Health Department issued a comprehensive “Overdose Prevention Plan” along with a user-friendly Roadmap to Reduce Drug Overdoses. Due to legal constraints, “supervised injection sites,” aka “overdose prevention sites,” remain in the planning stage. Instead, the City promotes “wellness hubs” where persons who use drugs can receive counseling and links to treatment and other services. The goals are to 1) increase the availability and accessibility of substance use services, 2) improve coordination among involved City departments, 3) strengthen community support for at-risk individuals, and 4) track and report overdose and drug use trends.  Notably, fentanyl test strips are distributed so that drug users can check if their batch contains fentanyl. Also, Narcan is widely dispensed to reverse opioid overdoses.

As the Fourth Wave floods the City, our interventions are faltering. Expenditures and programs have surged - but so have overdose deaths. This pattern points to flawed policies – or programs overwhelmed by the magnitude of the problem.

Looking at Policy Flaws

 In 2014, California Prop 47 reduced drug possession from a felony to a misdemeanor. Per the New York Times,” In San Francisco, law enforcement has responded by scaling back efforts against drugs, de-emphasizing incarceration and effectively allowing public drug use.” This laissez-faire enforcement dovetails with the current harm-reduction strategy. Harm-reduction does reduce deaths and injuries. But it’s proven incapable of reversing the mounting overdose deaths. One reason is that harm-reduction programs tend to honor the right to use drugs, and to enable safe drug use — rather than promoting treatment or recovery.  

Although the City adopted the Treatment on Demand Act in 2008, finding treatment means slogging through a maze of barriers. Plus, treatment programs are chronically understaffed. Accordingly, half of requests for treatment are unfulfilled.

On the other hand, whether services are offered to street users casually or after an arrest, very few accept. Last July, Mayor Breed announced that among “115 cited or arrested for public drug use. None have accepted services upon release…”  Granted, there may be better ways to draw users into treatment. But at this juncture, an acceptance rate of zero warrants stronger interventions.

A multi-agency crack-down of street dealers revealed another policy flaw - the City attracts “drug tourism.” At least 38% of 718 people cited or arrested for street drug offenses were out-of-county residents.  Out of 141 of those who received cash assistance from the City, 29% did not reside here.

Then we have the downside of the City’s Sanctuary Policy. Shielded from deportation are repeatedly arrested drug peddlers who entered the US illegally. A costly and burdensome work-around has been implemented with federal prosecutors but a policy revision is needed.

Enforcing Accountability

Despite the shaky evidence favoring compulsory treatment, frustration spurred 58% of City voters to pass Measure F.  It requires welfare recipients to be drug tested and enter treatment programs if they’re using illegal drugs. The deficit in treatment options needs fixing for this measure to work.


The Fourth Wave should prod revisions to public health and law enforcement approaches that aren’t working. Budgetary constraints will stifle local efforts.  More State and Federal resources are needed to keep the drug calamity from engulfing the City. Mayoral candidates are headed that way, calling for declaring a State of Emergency - and even California National Guard patrols to suppress open drug dealing. Meanwhile and perversely, overdose deaths are shrinking the pool of addicted persons in need of help.  

Dr. Derek Kerr is a San Francisco investigative reporter for the Westside Observer and a member of SPJ-NorCal. Contact:

April 6, 2024

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Derek Kerr
Dr. Derek Kerr

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