Madeleine Sweet’s fentanyl addiction started with an unexpected freebie. Already addicted to opioids and grappling with the sense that her life was going bottom-up as her student debts mounted, she was finding it difficult to access enough oxycodone and other opiates to satisfy her dependency.

So, in 2016, Sweet gravitated to the dark web. That’s where sellers were hawking designer drugs crafted to hijack the brain’s reward system, including mass-produced fentanyl, a synthetic opioid 50 times stronger than heroin. Sweet reached out to a seller for designer opiates and was sent a gram of fentanyl as a free sample with her purchase.

Soon, the sample arrived at her home in Monterey, California — a postage-stamp-sized bag of what looked like taupe-colored powdered sugar. Seconds after Sweet snorted the powder, an atomic-scale dopamine rush buried her in ecstasy. She came to a few minutes later with her head resting on her knees, her outlook altered. “I was like, now that I have this, I can just do everything I ever wanted to do, because I will enjoy it,” she says. “It just landed in my lap. And then it was hard to go back.” Once she started taking fentanyl, other opioids weren’t powerful enough to keep her from experiencing withdrawal symptoms.

Though she didn’t realize it at the time, Sweet was among millions of Americans who would get sucked into the drug’s undertow. Fentanyl was becoming more widely available Madeleine Sweet’s fentanyl addiction started with an unexpected freebie. Already addicted to opioids and grappling with the sense that her life was going bottom-up as her student debts mounted, she was finding it difficult to access enough oxycodone and other opiates to satisfy her dependency.

So, in 2016, Sweet gravitated to the dark web. That’s where sellers were hawking designer drugs crafted to hijack the brain’s reward system, including mass-produced fentanyl, a synthetic opioid 50 times stronger than heroin. Sweet reached out to a seller for designer opiates and was sent a gram of fentanyl as a free sample with her purchase.

Soon, the sample arrived at her home in Monterey, California — a postage-stamp-sized bag of what looked like taupe-colored powdered sugar. Seconds after Sweet snorted the powder, an atomic-scale dopamine rush buried her in ecstasy. She came to a few minutes later with her head resting on her knees, her outlook altered. “I was like, now that I have this, I can just do everything I ever wanted to do, because I will enjoy it,” she says. “It just landed in my lap. And then it was hard to go back.” Once she started taking fentanyl, other opioids weren’t powerful enough to keep her from experiencing withdrawal symptoms.

Though she didn’t realize it at the time, Sweet was among millions of Americans who would get sucked into the drug’s undertow. Fentanyl was becoming more widely available on the streets; in the early to mid-2010s, the drug began muscling its way into an opioid trade once dominated by heroin and prescription pills. By 2017, Homeland Security Investigations, the Department of Homeland Security’s investigative branch, was seizing almost 2,400 pounds of illicit fentanyl annually.

This shift has ushered in catastrophic results. Because fentanyl and similar lab-made compounds are so much more potent than other opioids, users’ risk of overdosing is significantly higher. Fentanyl overdose is now one of the most common causes of death among 18- to 49-year-olds in the U.S., and synthetic opioids have already claimed more American lives than the Afghanistan, Iraq, and Vietnam wars put together. The drugs continue to kill about 150 people in the U.S. each day.

Faced with this unprecedented death toll, scientists and care providers are embracing out-of-the-box solutions. Researchers are racing to perfect vaccines that can block the effects of fentanyl and similar drugs on the brain, neutralizing their euphoric effects as well as their deadly consequences. Meanwhile, many health care workers are adopting a harm-reduction approach to the crisis — offering opioid users services they need to stay safe and heal, rather than requiring them to abstain before they can get meaningful support.

Yet despite the evolution of the opioid treatment landscape, the way out of the crisis remains murky, in part because more studies are needed on which addiction recovery programs best promote long-term flourishing. To leave synthetic opioids behind, users must hurtle into what feels like a petrifying unknown and hope the ground rises up to meet them.

“A Perfect Setup for Overdoses”

Though fentanyl’s potency stands alone, the drug might never have sunk its tentacles so deep if not for the blockbuster rise in opioid prescriptions years earlier. When Purdue Pharma’s flagship drug OxyContin (a form of oxycodone) launched in 1996, the company spent hundreds of millions to drive its uptake, funding pain-management conferences, connecting patients to willing prescribers, and printing Get in the Swing With OxyContin CDs as a marketing ploy.

These kinds of campaigns proved a roaring success. By 2000, OxyContin alone was racking up nearly $1.1 billion in annual sales. And once people realized the pills drove a high that could be intensified by chewing or crushing them, they grew addicted in large numbers. As a result, U.S. overdose deaths from prescription opioids rose nearly fivefold, surging from around 3,400 in 1999 to more than 17,000 in 2017.

Medical providers started pulling back as they recognized the problem; U.S. opioid prescriptions dropped by 44 percent between 2011 and 2020. But millions of people who were already addicted simply looked elsewhere for the same high.

In the early 2010s, some of these prescription pill users transitioned to illicitly distributed narcotic pills or heroin, both of which then dominated the opioid trade. Soon, however, many switched to fentanyl. While pharmaceutical fentanyl has long been used to treat intense pain in hospitals and clinics, factories in China sprung up mid-decade to produce the compound illicitly — and some users sought it out because it offered a more readily available, intense high than other opioids.

Madeleine Sweet first began using fentanyl, in part, because she was having trouble finding opioids like oxycodone on the dark web. “It was getting more and more difficult to secure them, but also it was just getting outrageously expensive,” she says.

Drug distributors, meanwhile, have their own reasons for getting behind fentanyl: It offers massive profit margins, and it doesn’t require manufacturers to import and synthesize opium poppies that are challenging to cultivate.

The result has been an illicit marketplace overrun by one of the most potent drugs ever created, about 50 times stronger than heroin and 100 times stronger than morphine. “The supply from pill mills and [prescription] opioids was cut off, so people turned to heroin, which was very quickly replaced with fentanyl,” says Ryan Marino, an addiction medicine specialist at Case Western Reserve University School of Medicine. As the fentanyl wave has risen, opioid overdose deaths have climbed accordingly, nearly doubling between 2017 and 2021.

What compounds the danger further still is that thousands of Americans — many of them teenagers — buy fentanyl that masquerades as something else and ingest it without a clue what they’re taking. Not only does powdered fentanyl look nearly identical to heroin, but it can easily be blended into fake prescription opioid pills. “These pressed pills that are supposed to look like oxycodone, 30 milligram tablets, for the most part, they’re all just pressed fentanyl,” Marino says. “It’s just a perfect setup for overdoses.” In addition, fentanyl can be mixed with other illicit drugs such as cocaine, heroin, or methamphetamines — meaning that unless users test batches of these drugs with fentanyl test strips, the threat of unintentional overdose lurks with each high.

Fentanyl’s unique chemical structure has amped up the life-or-death stakes for anyone who tries the drug, knowingly or not. Fentanyl, heroin, and oxycodone all bind to the brain’s mu-opioid receptors, blocking pain signals and triggering the pleasurable release of dopamine. But fentanyl migrates to these receptors faster than other opioids because it passes more readily through the brain’s fatty tissues, a swift ingress that causes the potent systemic effects the drug is known for. Because fentanyl has more structural “branches” than most opioid molecules, it can also be tweaked in the lab to boost its strength further, spawning a series of designer fentanyl analogues.

Since fentanyl is so potent, the margin of error for dealers who cut their products with fillers like powdered lactose is terrifyingly narrow. Heroin blends of the past were about half drug and half filler, and small variations in that ratio were generally harmless. But with fentanyl, says Marino, a minor calculation glitch can mean the difference between life and death.

The threat of overdose is a constant background hum in fentanyl users’ lives. But what can feel even more consuming is the hour-by-hour hold the drug has on them, powerful enough to eclipse their best-laid plans. After Sweet’s first dose of fentanyl, her life continued to disintegrate from within. She lived with her parents in Monterey and with her ex-boyfriend at different times, unable to hold down a steady job as she focused on copping the drug. By 2021, she was living outdoors in a tent, spending most of her time in coastal Santa Cruz.

Her days on the streets became a blur: brief moments of otherworldly euphoria, punctuated by intense, heaving withdrawal sickness when she couldn’t secure more fentanyl. From time to time, volunteers in bright yellow vests would pass out granola bars and ask her if she needed help, but she turned them down.

“Right now, all I can focus on — all I can think about — is finding that feeling which I feel like feeling right now,” she wrote while taking shelter at a library. “I’m surrounded by so much pain — pain and trauma all squished into the tiny space between the needle’s point and your vein.”

Resisting the Drug’s Effects

As Americans continue succumbing to fentanyl, researchers around the country are working on treatments they hope can rescue users from addiction and early death. Among the most promising are vaccines designed to block the effects of fentanyl and other opioids on the brain so that users can no longer overdose or get high.

When synthetic opioids started surging in the drug marketplace several years ago, the U.S. government offered new funding for research that could help stem the crisis. Colin Haile, an addiction researcher at the University of Houston, submitted a proposal to the Department of Defense, describing his plans to develop a vaccine that would neutralize fentanyl.

Standard vaccines contain viral or bacterial components that cue the immune system to produce antibodies, preparing it to fight off targeted pathogens. Haile’s fentanyl vaccine works in a similar way — but instead of priming immune cells to resist pathogens, the vaccine-generated antibodies prime the body to resist the drug’s effects.

“If an individual consumes fentanyl after they’ve been vaccinated, those antibodies will bind to fentanyl and prevent the drug from getting into the brain,” Haile says. “That’s the key mechanism of action.” The vaccine has already demonstrated its mettle in the lab: Vaccinated rodents produced much higher levels of anti-fentanyl antibodies than control animals, and vaccinated animals did not get intoxicated when researchers dosed them with fentanyl.

Columbia University neurobiologist Sandra Comer has embarked on her own years-long quest to create opioid-blocking vaccines. After the oxycodone addiction wave hit, Comer and her colleagues set about creating a vaccine that would block oxycodone’s effects. In 2020, they launched the first human clinical trial of the jab. But as fentanyl took center stage and other opioid use dwindled, Comer decided to add a fentanyl vaccine to her arsenal. Like Haile’s, it generates antibodies that prevent fentanyl molecules from entering the brain. Comer is also working on another combination vaccine that would block the effects of heroin, oxycodone, and fentanyl.

Part of what motivates Haile and Comer is the prospect of delivering fentanyl users from addiction’s pull for long periods of time. At present, users who want to quit synthetic opioids can sign up for what’s called maintenance treatment — taking prescribed noneuphoric opioids, such as methadone, naltrexone, or buprenorphine, to stem their cravings for street drugs. This approach has proven effective: In one recent study of more than 40,000 opioid users, those who signed up for maintenance treatments with methadone or buprenorphine were less than half as likely as other users to overdose over a 12-month period.

The downside is that maintenance treatment requires frequent clinic visits, leading many users to drop out. Comer thinks a fentanyl vaccine could prove less burdensome to people while providing similar protection against addiction and overdose.

“The existing medications that are approved last for about a month,” she says. “We’re hoping that the vaccine will last longer, maybe on the order of two to three months before a booster shot is required.”

But before fentanyl vaccines can launch, they need to make it through clinical trials, which could prove a tall and drawn-out order. Haile’s fentanyl vaccine is slated to enter phase 1 human clinical trials this year, but since Comer is still completing oxycodone vaccine trials, her fentanyl jab may not be trial-ready until 2025. Even then, there are no guarantees that the vaccines will pass regulatory muster. “To determine definitively how enduring the antibody response to the vaccine is — that we’ll have to check,” Haile says.

Therapy and Services Are Needed Now

The vaccine trial apparatus may be whirring to life, but counselors and health care workers who witness fentanyl’s worst effects every day can’t afford to wait for results. As overdose death rates soar to new highs, they’re confronting challenging questions about how best to help their clients flourish. For many, the first priority has become keeping users alive at all costs, then helping them take concrete steps to turn their lives around.

This philosophy guides the staff of San Francisco’s Harm Reduction Therapy Center (HRTC), whose base of operations is steps from tent encampments beneath the Highway 80 overpass. Inside, HRTC’s Merlin service hub — open to all comers, regardless of addiction status — looks like an independent coffeeshop or co-working space, with a lofted ceiling and a spare, industrial vibe.

Adjoining the space’s main room, where people chat and greet each other’s dogs, are several small offices where drop-in clients can meet with mental health providers. Safe-use supplies, including clean syringes and naloxone (also known as Narcan) nasal spray to reverse opioid overdoses, are stacked in Tupperware containers for those who ask. “Our core grounding that we really operate from is making sure that people are healthy, safe, and alive, so they can decide with us whether they want to change their relationship with the drug,” says therapist Maurice Byrd, the center’s director of training and business operations.

HRTC also operates a constellation of pop-up sites around the city. On a Wednesday morning at one busy site near Victoria Manalo Draves Park, therapists speak with clients at folding tables and picnic benches. Among the day’s visitors is Jessi, 48, who’s been getting therapy and services at the site for over two years. While chasing after his muscle-bound dog, Sativa, Jessi lays out the challenges of life on the streets; his partner Beth, who he calls his rock, recently died. Through it all, site employees have helped him to plan for a better future. “There’s so much loss out there,” he says, his green eyes brimming. He gestures to the therapists, the benches, the congregated people. “This is the opposite of loss.”

Some policymakers have long objected to harm-reduction therapy for opioid users, suggesting that it enables their addiction. “I know people who are alcoholics, and I don’t buy them a bottle of whiskey,” Indiana county commissioner Mike Jones once said about his vote against a clean syringe exchange program.

Yet staggering numbers of overdose deaths are starting to turn the national tide in favor of harm reduction. In 2022, the Biden administration announced it was budgeting a historic $85 million federally to fund harm-reduction services. Some recovery programs are also getting on board with opioid addiction treatments that diverge from the traditional 12-step model, having recognized that many clients fall off the radar and die when asked to pledge total abstinence.

“We’re teaching people how to use Narcan. We’re giving practical ideas — like, ‘These are some things that you should do to be safer,’ ” says Karen Wolownik Albert, the CEO of Recovery Centers of America at St. Charles, Illinois. “We don’t want to discharge someone because they’re struggling. ‘Oh, well, you failed, come back when you’re ready.’ We want to keep working with them.”

For Sweet, a well-timed dose of naloxone turned out to mean everything. In the fall of 2021, she unknowingly took what she calls a “hot shot” from a batch of fentanyl that was too strong for her system, and passed out cold.

When she woke, she was surrounded by a circle of people in a big tent. They later told her what had happened: After she stopped breathing and her lips turned blue, someone had grabbed a naloxone spray dispenser, jammed it into her nostril, and pressed the plunger. “Without ready Narcan, I may have died even if they had called 911,” Sweet says. “There was not enough time. I likely would have been brain-dead.”

The Difficulty of Finding Durable Solutions

Squat red-and-white naloxone inhalers, stuffed in pockets and tucked behind restaurant counters, have saved so many people that they’ve come to seem as necessary as defibrillators for emergency use. What’s known at this point, says Harvard Medical School data scientist Mohammad Jalali, is that short-term harm-reduction measures, such as broad naloxone distribution, deliver strongly on their lifesaving potential.

These measures could decrease opioid overdose deaths by more than 10 percent over the next decade, according to Jalali’s data-driven SOURCE computer model, which predicts the ongoing evolution of the opioid crisis. The SOURCE model also shows that people perceive opioids as much riskier since fentanyl’s emergence, and that as a result, opioid overdoses are likely to decline in the next decade.

Yet even as the influx of new users diminishes, durable solutions to the crisis remain elusive in many ways. Jalali’s team developed their model with the U.S. Food and Drug Administration funding to help policymakers get a better grasp on which solutions offer the greatest return per invested dollar. But a lack of relevant research sometimes limits their analyses. While SOURCE shows that recovery support is essential to reduce opioid use rates, there isn’t all that much concrete data on which recovery approaches, besides medication maintenance, best help users escape addiction in the long run.

“We just don’t know much about how to improve recovery and how to have people in stable remission,” Jalali says. Though Manchester Metropolitan University public policy researcher Chris O’Leary has designed a broad meta-analysis that would directly compare the effectiveness of abstinence-based 12-step recovery programs to that of more permissive, harm reduction-based ones, the study has yet to be completed.

For now, recovering opioid users are climbing out of addiction any way they can, proceeding one handhold at a time. After her near-fatal overdose, Sweet had a decision to make: Stay on a course that could kill her within weeks, or choose another, however uncertain. Sensing Sweet was in grave danger, her mother tracked her down on San Francisco’s streets the day before Christmas Eve in 2021; Sweet collapsed in her arms, sobbing. Hours later, with her family’s support, she entered a medically supervised detox program.

Today, Sweet lives in her own apartment and works for the Mayor’s Office of Housing and Community Development in San Francisco, helping struggling city residents find affordable housing. She still gets disoriented sometimes when she thinks about the gulf between where she was three years ago and where she is now. “I have such profound gratitude,” she says. “The freedom of recovery and the things that come with it — they’re available to everyone.”

By working to loosen fentanyl’s grip, researchers could help touch off such upswings by the millions.

Elizabeth Svoboda is a writer based in San Jose, California and the author of What Makes a Hero?: The Surprising Science of Selflessness.

How to Detect and Respond to a Fentanyl Overdose

More and more, communities ravaged by synthetic opioids are opting for a pragmatic response — training the public, and opioid users’ family members, in rapid overdose response. Here’s four steps for helping someone who’s overdosed, based on materials from San Francisco’s Department of Public Health and the Substance Abuse and Mental Health Services Administration. (Whether or not you have naloxone, call 911 immediately.)

1. Signs of an overdose include unconsciousness and slow or shallow breathing. If someone is not responding, see if you can bring them back to consciousness by yelling something like, “Hey, are you OK?” If loud voice commands don’t work, clench your hand into a fist and rub your knuckles back and forth on the person’s sternum, the bony middle part of the ribcage. Because this feels uncomfortable, it can sometimes rouse people even when shouting doesn’t.

2. If the person still won’t respond and/or if they’re not breathing, administer naloxone (Narcan), an opioid antagonist that swiftly reverses fentanyl’s effects on the brain. (If you’re not carrying naloxone yourself, bars, restaurants, and stores may have it behind the counter.) Insert the nozzle of the naloxone inhaler partway into the person’s nostril and press hard on the plunger to dispense the dose. If two minutes have passed since the first dose of naloxone and the person has not revived, administer a second dose using a new dispenser.

3. If the person remains unresponsive, perform rescue breathing to deliver oxygen to the brain while you wait for emergency personnel to arrive. Pinch their nose shut, tilt their head back to open the airway, and direct two full breaths into their mouth followed by one full breath every five seconds, forming a seal to prevent air from escaping. (Many first aid kits and AEDs include a face shield that can be used to deliver rescue breaths while helping protect against disease transmission.) If you are doing this correctly, you will see the person’s chest rise and fall as you breathe.

4. If you can tell that the person has gone into cardiac arrest, combine rescue breathing with chest compressions, a technique known as CPR. With your arms extended, press hard and fast on the center of the chest. (The American Heart Association recommends doing this to the beat of the song “Stayin’ Alive.”) Continue doing this — in the form of 30 chest compressions followed by two rescue breaths — until the person responds, or emergency personnel arrives. — E.S.

This story was originally published in our July August 2024 issue. Click here to subscribe to read more stories like this one.