The Next Great Overdose-Reversing Drug Might Already Exist

Fentanyl-related substances have a bad reputation, but they could also save lives. In the US, a legislative battle to expedite research is heating up.

The overdose crisis is getting worse. Biblical-plague worse. The United States recorded more than 107,000 drug-induced deaths in 2021, up 28 percent from the previous year. Fentanyl has played a key role in this spike, with 64 percent of those deaths involving the synthetic opioid and its analogs. On the ground, harm-reduction groups are working to save lives with medications like naloxone, yet their efforts can only do so much. But they could soon have more tools to save lives: Scientists have discovered several fentanyl-related substances with potential to reverse overdoses. And this month, the US Congress has an opportunity to make studying these drugs and others like them easier.

Right now, getting approved to research fentanyl-related substances (often called “fentalogs” in the lab) requires leaping through onerous regulatory hoops. John Traynor, a pharmacology professor at the University of Michigan, is one of the relatively few researchers who have successfully gone through the approval process, which he calls “not impossible, but frustratingly slow.” It took one year to receive partial approval and another year for his lab to get full access to the fentalogs it needed. In a recent open letter to US president Joe Biden, more than a hundred other researchers called the process “prohibitively difficult.”

The reason for all this red tape? In 2018, the Trump Administration temporarily classified all fentalogs as Schedule I drugs, meaning they have no accepted medical use. (Fentanyl itself remained Schedule II, as it is a commonplace pain medication in hospitals.) The byzantine approval process to study these drugs reflects their status as potential hazards in the eyes of regulators; the US Drug Enforcement Agency (DEA) doesn’t want just anyone getting their hands on these substances, and wants to ensure they are handled properly. Traynor’s lab had to buy a new safe during their approval process, and received many in-person visits from local DEA officers.

This particular classification move was unprecedented. Typically, the DEA schedules individual drugs after a multistep evaluation process, looking at whether each one might have therapeutic value and potential for abuse. This time, it banned an entire group of molecularly related substances without evaluating them first. Thousands of these substances are thought to exist, many of which may be completely harmless, and some of which may be helpful. The ban even covers hypothetical fentalogs—substances that don’t exist yet, and for which there cannot possibly be any proof of danger: like, for instance, substances that could be vital to developing overdose-reversing medications. 

Despite this sweeping, unorthodox approach, the Schedule I order was not especially controversial in Washington. In fact, it had bipartisan support. (The Biden administration actually recommendedpermanent Schedule I classification for these substances last year.) 

This stridency reflects the national mood toward fentanyl. Politicians have been desperate to address the overdoses ravaging their constituencies. (Some have even called for the drug to be labeled a “weapon of mass destruction.”) Prior to the temporary scheduling, drug traffickers had been introducing fentalogs to the streets at a rapid clip; by changing the molecular structure slightly, they had created substances that were harder for law enforcement to detect. The reclassification looked like a straightforward way to stymy traffickers’ efforts. Since Biden took office, this temporary Schedule I policy has been repeatedly extended by Congress. It’s up for renewal once again, as the current extension expires at the end of this year. 

Critics say the Schedule I classification is heavy-handed, based on fear rather than evidence. “It bypasses science,” says Maritza Perez, a director at the Drug Policy Alliance, a nonprofit focused on drug policy reform. Frustrated by this blanket ban and eager to develop new overdose treatments, a growing number of scientists, doctors, and other researchers are pushing back. 

“A classwide ban based on chemical structure alone would preclude a lot of research that could lead to life-saving medications,” says Gregory Dudley, a chemistry professor at West Virginia University and one of the co-authors of the open letter to Biden. In that letter, Dudley and other scientists argue that permanent Schedule I status could “inadvertently criminalize” important tools to fight the overdose crisis.

Dudley supports a bill introduced last week by US senator Cory Booker (D-New Jersey) called the Temporary Emergency Scheduling and Testing (TEST) Act, which would temporarily extend Schedule I classification again but also require the government to evaluate individual fentalogs, descheduling those with therapeutic uses or without risk of abuse. Booker is hopeful he can pitch his bill as a common-sense approach to the issue. “This bill strikes a middle ground to ensure that we are doing all we can to save lives,” he told WIRED by email. 

Even some experts who support permanent scheduling recognize that the status quo doesn’t work. “I believe that the fentanyl-related substances should be permanently put into Schedule I. But I also very strongly believe that the research on Schedule I drugs—and this is more than just the fentanyl-related substances—should be made easier,” says Victor Weedn, a forensic pathologist and professor at George Washington University. In addition to fentalogs, drugs like cannabis and psilocybin are also classified as Schedule I, which has impeded research on those substances as well.

The discovery of a new overdose-reversal medication would be a major victory for public health. Naloxone—often referred to by its brand name, Narcan—is currently the only drug widely available for reversing opioid overdoses. Molecularly similar to the opioid oxymorphone, naloxone works by binding to opioid receptors, blocking the effects of other opioids. It isn’t a silver bullet, but it has become an important tool for keeping people alive. It is often in short supply, though—and can be expensive.

“Anything we can do that would increase the variability of products on the market could potentially help overcome supply chain issues and hopefully drive down prices,” says Stacy McKenna, a harm reduction fellow at the libertarian-leaning think tank the R Street Institute. “And there might be something that works better to help reverse fentanyl overdoses.”

While naloxone can reverse fentanyl overdoses, it’s not always as effective as it is with less-powerful opioids. “One problem is re-narcotization,” Traynor says. A dose of naloxone that would revive someone who took too much heroin might wear off for someone who took fentanyl, causing their overdose symptoms to return. This means multiple doses of naloxone can be necessary to stop fentanyl overdoses—bad news for people who might have just a single dose at hand. If there’s another option out there more efficient at specifically reversing fentanyl overdoses, it could have a seismic lifesaving effect.

During a congressional hearing last year, Douglas Throckmorton, the US Food and Drug Administration’s (FDA) deputy director for regulatory programs, revealed that the agency knew of at least one fentalog with the potential to reverse overdoses. An FDA spokesperson told WIRED by email that the agency has studied “fewer than 35” fentanyl-related substances thus far; they did not provide any additional information about the substance Throckmorton mentioned. But there have already been other promising developments. At Traynor’s University of Michigan lab, his team has already discovered several other fentalogs with potentially overdose-reversing properties, with two especially strong candidates; they aim to develop a proprietary overdose-reversal medication based on these substances.

As it took years to complete the approval process, this hasn’t been a particularly fast-moving project. “We’ve only been working at it for a year or so, and we’re a tiny team,” Traynor says. So far, they have studied only the substances in biochemical assays; they are discussing what tests on mice would look like, but aren’t at that stage yet. It’s enormously exciting work, but still in its early days.

As Traynor’s team continues its work, other scientists like Dudley continue to advocate for easier access to fentalogs. If the TEST Act passes, more researchers will be able to jump into the race to create a new breed of overdose reversal meds, heightening chances of success.

But it’s crunch time: Because the renewal of the temporary Schedule I order expires at the end of the year and the congressional session ends a few days later, the bill will have to pass this month, possibly as part of an omnibus bill. Otherwise, Booker would have to reintroduce it in 2023. As the overdose crisis continues, every day that passes without new tools is a lost day.

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