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The New Fentanyl and Speedballing Crisis of 2024

Developing medicines that help with fentanyl addiction and overdose.

Key points

  • Fentanyl in counterfeit pills or smoked alone or with methamphetamine are changing the overdose epidemic.
  • Inexperienced (low-tolerance) fentanyl smokers, users or speedballers, are at high risk of overdose.
  • Pre-existing Depression, COVID, heart disease, and liver disease lead to a greater risk of overdose death.
  • Prevention and education are needed while NIDA supports developing vaccines and new medications.

The last heroin epidemic in the ‘70s and early ‘80s led to speedballing (combining heroin with cocaine). Freebasing was an alternative to intravenous use and its associated needle risks. It was replaced by crack cocaine, which was easier to mass-produce and distribute. The current epidemic started with prescription opioids and moved to heroin, then fentanyl, and lastly, speedballing. Fentanyl has flooded the U.S. and is extremely cheap — $10/gram. This new smoking overdose risk is moving from San Francisco throughout the rest of the country.

This new phase of the opioid overdose crisis focuses on young naïve users. They are sold fentanyl-laced opioid-pain pills, counterfeit Adderall, and other drugs attached to a Trojan horse of fentanyl. As for vapers and smokers, they speedball fentanyl with methamphetamine via fentanyl smoking. Difficulty injecting, fear of needles, hepatitis, and HIV risks, as well as fear of overdose, seemingly motivated this transition from injecting to smoking. Smoking encourages inhalation of large doses of fentanyl — approximately 50 mg of pure fentanyl per day.

When we studied crack, intranasal cocaine, and intravenous use of cocaine in the 1980s, we were surprised to discover smoking was equivalent to injection in speed to the brain. Taking pills orally has the slowest response but most users want to experience the drug’s effects as quickly as possible. Users may mistakenly believe they are “safe” from overdoses if they smoke drugs like fentanyl. Younger needle-adverse new users have learned to smoke and vape and are less fearful of smoking fentanyl. However, it is still very possible to overdose as smoking fentanyl today often means higher doses, plus smoking the previous smoker's drugs piggy-backed, including fentanyl and meth residues.

Experts are concerned about more fentanyl overdoses among new smokers of fentanyl as the potency of the drugs and new users’ much lower tolerance (compared to that of experienced users) collide.

Nora Volkow, MD, director of the National Institute on Drug Abuse
Source: NIDA

Agnostic Respiratory Stimulants Are Being Developed

Narcan (naloxone) was developed 50 years ago, has limitations, and is ideally suited to reverse heroin and morphine. It was not designed to treat fentanyl overdoses.

With fentanyl, the window of time for saving a person is much shorter than with heroin. Some drugs bind with a higher affinity to opioid receptors than others. When they bind with higher affinity, there’s a greater probability that the drugs “stick” to the binding site. Fentanyl is catalyzing the death epidemic because of its extremely high intrinsic efficacy and affinity for opioid receptors.

Shallow breathing, respiratory depression, and not breathing are major issues in overdoses. The fentanyl crisis, speedballing, and polysubstance ingestion with agents from multiple respiratory depressant classes cause respiratory chaos. Reversing them is difficult, creating an unmet need for treatment medicines stimulating breathing.

Experts are concerned because a fentanyl/fentanyl analog overdose requires swift, timely, and effective treatment, whether drugs were speedballed or used alone. Fentanyl overdoses are often catastrophic because of the rapidity of overdose onset and the very narrow window of time necessary for reversal. Direct comparisons are lacking but some early comparisons suggest the medication nalmefene has advantages in treating respiratory depression fentanyl overdoses.

A new paper directly compared intranasal naloxone vs. nalmefene for fentanyl overdose. The authors focused on respiratory depression and cardiac arrest. Using a validated translational animal model, the study quantitatively predicts opioid-induced respiratory depression and cardiac arrest. In this study, intranasal (IN) nalmefene significantly outperforms intranasal naloxone in reducing cardiac arrest rates following synthetic opioid overdoses. A single dose of IN nalmefene substantially reduced cardiac arrest incidence, whereas four doses of IN naloxone were required for similar outcomes. This research underscores the potential of IN nalmefene as a new, underutilized FDA-approved intervention to fight the synthetic opioid crisis.

However, it’s important to have more than simulations; a real and direct comparison in overdoses treated with intranasal Narcan or Opvee is needed. But this will take years. We desperately need the established Narcan distribution system and current inventories of naloxone at home and in the community to save lives. Theoretically, we could save more lives if nalmefene were added to the original large dose of intranasal administration of Narcan by EMTs — or at least, after naloxone alone has failed. This is an issue that should be studied.

Overdose Risk Factors

What factors increase the risks of fentanyl overdose deaths? The general health of the user is important. Pre-existing conditions like depression, suicidal thoughts, COVID-19, heart disease, chronic obstructive pulmonary disease (COPD), liver disease, sleep apnea, and severe obesity have a greater risk of death. Individuals who never used opioids before or maybe used once or twice have a much greater risk for overdose and death than “old hands.” (However, even long-term users overdose.) The quantity and quality of the opioids taken is significant and “more," or a higher quantity, is not better. Fentanyl is a high-risk drug for overdoses: About 80% of opioid fatalities involve fentanyl. Multiple opioids include fentanyl, complicating opioid overdose reversal. Another key factor is whether the person also used depressants like alcohol or benzodiazepines along with fentanyl, and if stimulants were also used. The reason: When additional drugs are taken, this complicates overdose reversal, especially outside the ER. In addition, whether the patient has developed a tolerance to opioids is significant. Last, the longer the time between when symptoms like respiratory depression and stupor are present and attempts to intervene occur, the worse the prognosis.


In the ever-changing opioid epidemic, it’s difficult for researchers and treatment experts to keep up, but they’re trying. While new vaccines are hopefully developed which might prevent both use and overdose, new antidotes to drug poisoning and new medicines for opioid use disorder (OUD) are being tested, as are ibogaine, psilocybin, and other psychedelics for treatment.

We should focus on what we can do now and how to do it better. We should evaluate whether to modify our initial Narcan overdose reversal dose and consider whether to add Opvee to treat fentanyl overdoses not immediately responding while we await comparable efficacy data. We should do better at motivating patients whose overdoses were reversed to enter medication-assisted treatment with one of the three FDA-approved medications for OUDs. We should continue lifesaving and relapse-preventing OUD treatments, as early data on MAT treatment discontinuation has shown relapse and overdose risks returning to pre-treatment levels when treatment is discontinued. We should also revisit and support national prevention efforts. In a previous post, I highlighted the “One pill can kill” campaign, and CADCA and ORCA prevention efforts. At the grassroots levels, there are movements to support teens who choose to be drug and alcohol-free, like One Choice, which supports the 64% of high school seniors who have not used any substance in the past month and the 36% who haven’t used one in their lifetime.

Overdose reversal is important but always a last resort. Research and new treatment development, early identification, and treating substance use disorders (SUDs) and overdoses are essential, as is preventing drug use and reducing harm.


Ciccarone D, Holm N, Ondocsin J, Schlosser A, Fessel J, Cowan A, Mars SG. Innovation and adaptation: The rise of a fentanyl smoking culture in San Francisco. PLoS One. 2024 May 22;19(5):e0303403. doi: 10.1371/journal.pone.0303403. PMID: 38776268; PMCID: PMC11111043.

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Skolnick P. Treatment of overdose in the synthetic opioid era. Pharmacol Ther. 2022 May;233:108019. doi: 10.1016/j.pharmthera.2021.108019. Epub 2021 Oct 9. PMID: 34637841.

Ivsins A, Bonn M, McNeil R, Boyd J, Kerr T. A qualitative study on perceptions and experiences of overdose among people who smoke drugs in Vancouver, British Columbia. Drug Alcohol Depend. 2024 May 1;258:111275. doi: 10.1016/j.drugalcdep.2024.111275. Epub 2024 Mar 29. PMID: 38581922; PMCID: PMC11088499.

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