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, 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. University of Michigan pharmacology professor John Traynor 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 additional year for his lab to get full access to the fentalogs it needed. In a recent open letter to 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, which means 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 in the eyes of regulators as potential hazards; the US Drug Enforcement Agency 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 multi-step 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 recommended a permanent Schedule I classification for these substances last year.)
This stridency reflects the national mood towards 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 street at a rapid clip; by changing the molecular structure slightly, they created substances which 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 non-profit 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.
Last year, during a Congressional hearing, Douglas Throckmorton, the US Food and Drug Administration’s 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 only studied the substances in biochemical assays; they are discussing what tests on mice would look like, but aren’t at that stage just yet. It’s enormously exciting work, but still in 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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