The concept has long tantalized scientists: harnessing the power of antibodies to block the dangerous effects of heroin, cocaine and nicotine, substances that have wrecked or ended millions of American lives.

Despite years of efforts that have failed to yield viable vaccines or lab-made antibody treatments, research is accelerating as the nation grapples with an unprecedented drug crisis — more than 100,000 Americans died of overdoses in each of the past two years, fueled chiefly by the synthetic opioid fentanyl.

Backed by millions of dollars in federal funding, researchers envision vaccines and monoclonal antibody treatments as supplementing opioid treatment and overdose medications, though it could be years before the prospective therapies become available.

The federal government recently awarded an additional $14.8 million for research into a monoclonal antibody that would target fentanyl — the nation’s deadliest street drug — by binding to its molecules before they can invade the brain and shut down breathing. Cessation Therapeutics, a North Carolina biotech company, touts its monoclonal antibody as a way both to prevent overdoses and to treat overdoses and opioid addiction.

“It sponges it up — it’s like a Pac-Man,” said Andrew C. Barrett, chief scientific officer at Cessation Therapeutics, which recently began the nation’s first government-approved clinical trial to test in people a monoclonal antibody infusion targeting fentanyl.

Monoclonal antibodies — proteins brewed from cells in giant vats under controlled conditions — have been in use for decades, transforming the treatment of cancer and autoimmune diseases, even though the drugs are expensive. Before coronavirus vaccines debuted, antibody drugs proved effective against the pandemic pathogen, a high-profile showcase of their potential to treat other infectious diseases.

Clinical trials are also ongoing into a monoclonal antibody treatment for methamphetamine, the stimulant increasingly being used with fentanyl.

At the same time, Food and Drug Administration-approved clinical trials are continuing for a vaccine targeting oxycodone, the prescription painkiller that helped spawn the country’s opioid crisis. Researchers are also developing vaccines against heroin and fentanyl.

The efforts reflect the urgency of the drug crisis, but that urgency crashes up against a harsh reality: Similar research has been stymied for decades. Research is expensive, and that doesn’t count the cost for a company to bring an antibody or vaccine to market. It is also time-consuming and time-sensitive because the illicit-narcotics landscape evolves quickly, with new synthetic substances surfacing faster than researchers can study them. And skeptics argue that drug users won’t buy in, or will simply switch to other substances — if they can even afford the high price of antibody treatments.

“People have to say they want to be injected, and they have to choose to keep coming back for each injection or infusion,” said Keith Humphreys, a Stanford University professor of psychiatry and former White House drug policy adviser. “The vaccines do nothing to reduce craving or withdrawal or to motivate anyone to return for more care.”

Ryan Marino, an addiction specialist and assistant professor at Case Western Reserve University School of Medicine, pointed out that the medication buprenorphine exists to curb opioid cravings, and Vivitrol, a monthly non-opioid shot that binds to receptors in the brain, blocks the euphoria produced by opioids.

Marino argued that resources should be spent on expanding access to existing medications and the overdose reversal drug naloxone, not on vaccines. “Pouring money and resources into moonshots like that have failed time and time again. It’s a little disappointing to me,” he said.

A long history of research

For decades, scientists have sought ways to use antibodies to stop the harmful effects of street drugs. In the 1970s, researchers created a vaccine that blocked the effects of heroin in a rhesus monkey trained to self-administer drugs. The research, published in the journal Nature in 1974, was promising — but also showed that high doses of heroin could thwart the antibodies.

Research waned with the introduction of methadone, an opioid medication that treats heroin cravings. In later decades, researchers armed with greater understanding of the science of addiction focused on public health threats such as cocaine and nicotine.

A vaccine administered by shot would coax the immune system to create antibodies to fend off an invader. But instead of a virus, the target would be the molecules of addictive drugs. Normally, those molecules are too small to spark creation of antibodies. To solve that problem, researchers attach a similar-looking molecule onto a larger protein, essentially tricking the immune system into creating antibodies.

Over the years, vaccines haven’t generated enough antibodies. And when it came to a vaccine against nicotine, antibodies didn’t bind tightly enough to the molecules, which linger in the body for a long time, said Kim Janda, a Scripps Research chemist who has worked on vaccines and monoclonal antibodies for decades.

“I’d guess there’s probably been about 30 or 40 nicotine vaccines that have been attempted, and they just have all failed,” Janda said.

One highly touted potential vaccine, NicVAX, fared no better than a placebo in a clinical trial of 1,000 smokers, its developer revealed in 2011.

Efforts to make a vaccine against cocaine have sputtered, too. In one case, trial results published in 2014 showed that only about 63 percent of a group of 150 vaccinated people achieved sufficient levels of antibodies, said Thomas R. Kosten, a Baylor College of Medicine professor of psychiatry and immunology who ran the trial.

“That wasn’t enough for FDA approval,” Kosten said. “They wanted more like 80 or 90 percent.”

Kosten is working on a fentanyl vaccine he hopes will soon be ready for a clinical trial.

Researchers said they think fewer vaccine-generated antibodies will be needed to attack fentanyl.

The drug — while extremely potent — is typically ingested in smaller quantities, said Marco Pravetoni, who heads the University of Washington Center for Medication Development for Substance Use Disorders and Overdose and is working on vaccines for fentanyl and heroin. A vaccine could prove especially helpful for users of drugs such as cocaine who fear it might be tainted with fentanyl, Pravetoni said.

“This vaccine could be almost perfect for the occasional user,” said Pravetoni, who is also working on the oxycodone vaccine clinical trial along with Columbia University researchers.

Pravetoni is investigating a fentanyl monoclonal antibody, too, which some scientists believe holds greater promise than vaccines.

Proponents argue that monoclonal antibodies — administered by IV infusions or shots — can be designed to act overwhelmingly and fast, while it may take weeks and several shots for vaccines to generate enough antibodies to counteract a drug.

“The monoclonal antibody in many ways is a safer bet,” said Nora Volkow, director of the National Institute on Drug Abuse, which has funded research into both.

Not everyone is so enamored. Skeptics note that monoclonal antibodies would last only a few weeks. Vaccines would last longer and cost less — even if they are less effective. Synthesizing, infusing and monitoring antibody treatment might simply prove too expensive, said Humphreys, of Stanford.

“That cost might be justifiable for meth or cocaine, for which we have no medication. But who — a patient, private insurer, Medicaid — is going to pay for that for opioids when we have a number of cheaper and effective alternatives available?” Humphreys said.

And questions persist about whether users most at risk of overdose would even want frequent treatments. Fentanyl users could switch to another opioid with a different chemical makeup. A cocaine user might move to another stimulant such as meth. Or use a lot more cocaine.

“If someone is determined to take cocaine, they will be able to overcome the antibody. But they’ll have to use a lot more cocaine to do it. So it really will only work for people who are motivated to quit,” said Andrew B. Norman, a University of Cincinnati researcher developing a monoclonal antibody to target cocaine.

The quest to treat meth use

Clinical trials are further along for a monoclonal antibody treatment for meth, which causes overdoses looking nothing like what opioids trigger. A chronic user taking too much meth can experience agitation or paranoia, elevated body temperature, chest pain, a rapid heart rate and heart failure.

InterveXion Therapeutics, a biotech company in Little Rock, has received about $60 million in federal funding and completed a pair of Phase 2 trials. In one study, dozens of participants were given small doses of meth along with the antibody to gauge how it alters concentrations of the stimulant.

Researchers found that the level of meth in the bloodstream actually increased, a signal that the antibodies were pulling meth molecules from the brain and heart, said W. Brooks Gentry, the company’s chief medical officer. The molecules then leave the bloodstream and end up being metabolized through the liver and kidney, he said.

Another trial involving the monoclonal meth treatment is being conducted in conjunction with cognitive behavioral therapy.

Gentry cautioned that the antibody is designed to significantly reduce the effects of meth, not cravings.

“We’re trying to help the number of attempts [patients] need to stop using,” Gentry said. “They don’t get the positive reinforcing effects. It feels just like they haven’t taken anything.”

The company estimates it would take at least five more years and additional studies to seek regulator approval. Gentry said that while it’s too early to forecast how much an infusion might cost with a future approval, right now it might run between $1,500 and $2,000.

Cessation Therapeutics touts its monoclonal antibody as a way to prevent overdoses from fentanyl and related substances. Fentanyl — up to 50 times as potent as heroin — is the leading cause of death for Americans 18 to 49, according to a Washington Post analysis. An estimated 5.6 million people older than 12 suffered from opioid-use disorder within the past year, according to 2021 federal survey data.

Opioids attach to brain receptors and can slow or stop breathing and cause death. The monoclonal antibody would bind to fentanyl molecules before they can slip through the layer of tightly locked cells that keeps substances from entering the brain, said Barrett, the company’s chief scientific officer.

The antibodies would also excise molecules that make it to the brain, reversing an overdose, he said. Experts say the treatment wouldn’t be realistic for emergency use. Naloxone, often deployed in a nasal spray now available over the counter, is commonly used by emergency responders, family and even passersby to quickly revive users.

Instead, Barrett said, researchers envision the antibodies as an added layer of protection that will prevent future overdoses and act as an adjunct to treatment drugs.

The federal funding announced Oct. 18 — which adds to $7.1 million previously granted for research into the infusions, which the FDA approved for a first clinical trial in July — would pay for research into a monoclonal antibody that could be administered by shots. Scientists from the Integrative Neurochemistry Laboratory at McLean Hospital, a psychiatric hospital in Boston, will test the antibody in animals.

So far, six study subjects with no addiction problems have received the antibody. No adverse reactions have emerged, although data has yet to be released, Barrett said. A second-phase trial would entail giving the antibody, then administering medical-grade fentanyl, to healthy participants. A “pivotal” study would involve patients already beset by opioid use. If the trials succeed, the company could ask the FDA for accelerated approval by the first half of 2026, Barrett said.