In 2018, the Trump administration and the Drug Enforcement Administration issued a temporary emergency order that, for the first time, placed an entire class of drugs, referred to as “fentanyl-related substances,” (FRS) on Schedule I, the most restrictive tier of the Controlled Substances Act. Not only is this unprecedented classwide approach to scheduling failing to make a dent in overdose deaths, it contributes to overcriminalization and hinders research. Congress has extended the policy half a dozen times and continues to debate the issue, but scientists from all over the country are calling on the government to instead test individual FRS. Here’s why.

Drug Scheduling 101

The established standard for scheduling substances in the United States is a multi-step process that assesses chemical structure, pharmacological effects and public health risks associated with each substance. The Federal Analogue Act, passed in 1986, ensures that this process does not prevent law enforcement from investigating or prosecutors from prosecuting novel drugs.

What are FRS?

FRS are similar in chemical structure to fentanyl, a Schedule II analgesic drug that is 50 to 100 times stronger than morphine. Due to their high levels of potency, illicitly manufactured fentanyl and many FRS are key drivers in the ongoing overdose crisis. Although there are an estimated 4,800 potential FRS, federal law enforcement agencies have encountered and identified approximately 44—less than 1 percent.

Why test individual FRS?

As seen above, the definition of FRS depends exclusively on chemical structure. However, a drug’s chemical structure and its behavior are not one-and-the-same. Even “simple changes to a chemical’s structure can impart substantial changes in its activity.” For example, although naloxone is chemically similar to morphine, it does not produce sedating, euphoric or analgesic effects. Rather, naloxone is a medication used to reverse overdoses because it blocks other opioids from binding to the necessary receptors. Furthermore, chemical structure does not indicate whether the substance will act as an antagonist (like naloxone), a partial agonist (like the treatment medication buprenorphine) or a full agonist (like heroin or methadone, also a treatment medication). If we schedule the whole class of drugs without performing important tests to better understand the real effects of individual substances, we risk missing out on life-saving scientific discoveries.

We need new therapies

Fentanyl and FRS present a challenge for overdose response and substance use disorder treatment. While traditional medications, including the overdose reversal drug naloxone and treatment therapeutics such as buprenorphine and methadone, are saving lives in the FRS-driven overdose surge, they are less effective against FRS compared to heroin and other opioids for which they were originally approved. As such, there is an urgent need for continued scientific research into novel drugs that could be more effective at addressing the risks associated with FRS and other highly potent synthetic opioids.

Among the thousands of potential FRS, there are likely myriad undiscovered reversal agents and treatment options. Of the roughly 44 FRS the government has already identified, 25 had been evaluated as of December 2021. Of these, some appear to be completely inert while at least one may act as an overdose antidote or treatment medication.

What does this mean for policy?

When these various factors are all taken into account simultaneously, it becomes clear that testing individual FRS is an essential part of policy. It will allow not only for more precise decisions around the proper scheduling of each substance, but also will enable faster discovery of new tools with which to battle the overdose crisis.

Image credit: terovesalainen