Science Fentanyl Trials 521677654

The next big overdose drug may already exist

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

The reason for all this bureaucracy? In 2018, the Trump administration temporarily classified all fentalogs as Schedule I drugs, meaning they have no accepted medical use. (Fentanyl itself remained on Schedule II, as it is a common pain reliever in hospitals.) The Byzantine approval process for studying these drugs reflects their status as potential dangers in the eyes of regulators; the US Drug Enforcement Agency (DEA) doesn’t want anyone to get their hands on these substances and wants to make sure they are handled properly. Traynor’s lab had to purchase a new safe during the approval process and received many in-person visits from local DEA officials.

This particular classification move was unprecedented. Typically, the DEA programs individual drugs after a multi-step evaluation process, testing whether each may have therapeutic value and potential for abuse. This time it banned a whole group of molecularly related substances without evaluating them first. There are thought to be thousands of these substances, many of which may be completely harmless and some of which may be beneficial. The ban also covers hypothetical fentalogs, substances that do not yet exist and for which there can be no evidence of danger: such as, for example, substances that could be vital for the development of overdose drugs.

Despite this radical and unorthodox approach, the Schedule I order has not been particularly controversial in Washington. Indeed, it had bipartisan support. (The Biden administration actually recommended a permanent Table I classification for these substances last year.)

This screech reflects the national mood towards fentanyl. Politicians have desperately tried to address the overdoses that have ravaged their constituencies. (Some have even called for the drug to be labeled as “weapon of mass destruction.”) Prior to the temporary programming, drug traffickers had been introducing fentalogs through the streets at a rapid pace; by slightly modifying the molecular structure, they had created substances that were harder for law enforcement to detect. The reclassification seemed like an easy way to thwart the smugglers’ efforts. Since Biden took office, this temporary Schedule I policy has been repeatedly extended by Congress. It is 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. “Bypass the science,” says Maritza Perez, director of the Drug Policy Alliance, a nonprofit focused on drug policy reform. Frustrated by this general ban and eager to develop new treatments for overdose, a growing number of scientists, doctors and other researchers are resisting.

“A class-wide ban based only on chemical structure would preclude much research that could lead to life-saving drugs,” 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 Schedule I’s permanent status could “inadvertently criminalize” important tools for combating 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 would also require the government to assess individual fentalogs, deprogramming them with therapeutic uses or without risk of abuse. Booker hopes he can present his own bill as a common-sense approach to the matter. “This bill is a middle ground to ensure we’re doing everything we can to save lives,” he told WIRED via email.

Even some experts who advocate permanent programming acknowledge that the status quo doesn’t work. “I believe that fentanyl-related substances should be permanently placed on Schedule I. But I also strongly believe that research on Schedule I drugs, and this is not just fentanyl-related substances, should be facilitated,” says Victor Weedn, a forensic pathologist and professor at George Washington University. In addition to fentalogs, drugs such as cannabis and psilocybin are also classified in Schedule I, which has also hampered research on these substances.

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

“Anything we can do to increase the variability of products in the market could potentially help overcome supply chain problems and hopefully lower prices,” says Stacy McKenna, harm reduction researcher at the think tank of libertarian orientation R Street Institute. “And there may be something that works better to help reverse fentanyl overdoses.”

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

During a congressional hearing last year, Douglas Throckmorton, deputy director for regulatory programs for the United States Food and Drug Administration (FDA), revealed that the agency was aware of at least one fentalog with the potential to reverse the overdoses. An FDA spokesperson told WIRED via email that the agency has studied “fewer than 35” fentanyl-related substances so far; they did not provide further information on 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 particularly strong candidates; aim to develop a patented overdose reversal drug based on these substances.

Because the approval process took years to complete, this project didn’t go particularly fast. “We’ve only been working on it for about a year and we’re a small team,” says Traynor. So far they have only studied the substances in biochemical tests; they’re discussing what the mouse tests would look like, but they’re not there yet. It’s a hugely exciting job, but still in its infancy.

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 generation of overdose reversal drugs, increasing the chances of success.

But it’s crunch: As the Schedule I interim order renewal 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 day lost.