Safer Solutions: The Challenges of Regulating Chemical Analogs

Our brains love to sort things into categories to help us process the enormous amount of information we take in at every moment. But just because things are similar in one way doesn’t mean they are similar in every way. Think about transportation: Cars, bikes, trains, and airplanes are all modes of transportation, but they are also distinctly different machines. The same is true for chemicals and their analogs.

Analogs are chemicals that are functionally and/or structurally similar to one another, though not identical. The small differences in chemical structure can have a big impact on the way they affect the body—for example, a minor structural change might make an analog’s effects stronger or weaker than the original chemical or cause entirely different effects on the body. In substance regulation, these differences and similarities lead to an important question: Should policymakers regulate entire categories of substances based on their structural similarities or address each substance individually? Let’s look at two divergent examples: fentanyl and nicotine.

Regulating Fentanyl Analogs

Fentanyl analogs are the subject of considerable policy debate. As fentanyl has spread through the illicit drug supply, it has left an unprecedented trail of damage—including increasing overdose rates to historic highs. In fact, some policymakers are concerned that new fentanyl analogs could cause another wave of the opioid epidemic.

In 2018, in an effort to prevent new fentanyl analogs from permeating the illicit market, the Drug Enforcement Administration temporarily placed all “fentanyl-related substances” (i.e., substances with a similar chemical structure to fentanyl, regardless of their effects on the body) on Schedule I. Schedule I substances are defined as having high abuse liability but no currently accepted medical use. They are also illegal to possess, manufacture, or sell. This class-wide scheduling became permanent when Congress passed the HALT Fentanyl Act in 2025. Federally scheduling all analogs of a drug is a new approach that bypasses the Controlled Substances Act (CSA) requirement that each substance’s effects be assessed prior to scheduling. It’s worth noting that the Controlled Substances Analogue Enforcement Act of 1986 allows prosecution for possession, sale, or manufacture of analogs that are chemically and functionally similar to a substance already on Schedule I or II. The Analogue Enforcement Act does not negate the CSA’s requirement that each substance undergo a full evaluation of its effects before being officially scheduled. Class-wide scheduling accomplishes the same thing when it comes to enforcement; however, this approach has some drawbacks.

While class-wide analog regulation tends to give law enforcement and/or regulatory agencies more latitude in an ever-changing legal or illicit marketplace, it may also stifle innovation. Regulating all structural analogs at once helps prevent regulatory “whack-a-mole” situations in which policymakers must constantly address the newest version of a chemical as it emerges, but it can miss functional analogs (chemicals that produce similar effects, with or without similar structure). Also, since there can be many analogs of one chemical—each one producing different effects than the original—drug developers sometimes use analog-based drug discovery to identify novel drug candidates. For example, naloxone, the drug that reverses opioid overdoses, is structurally similar to morphine—a Schedule II opioid. We know fentanyl has medical uses, which suggests that some analogs could also have medicinal benefits and possibly lower potential for abuse. However, by placing all fentanyl analogs on Schedule I, the federal government has made it harder for researchers to investigate medical uses for them. Furthermore, if a medical use is found for a scheduled substance, changing its schedule is a long and strenuous process.

Regulating Nicotine Analogs

Products containing nicotine analogs that mimic the effects of nicotine, the chemical in tobacco products that causes dependence, are an emerging regulatory challenge. The Food and Drug Administration (FDA) regulates tobacco products via its regulatory authority over “any product made or derived from tobacco, or containing nicotine from any source.” But because nicotine analogs are different from nicotine, they sit in a regulatory grey area in which the FDA can exert minimal oversight. Nicotine analogs have unknown health effects and abuse liability, which could present new risks to consumers. Lawmakers and regulators must now decide how to react to the changing marketplace. This situation echoes challenges the FDA faced when synthetic nicotine products hit the market around 2021. It wasn’t until 2022, when Congress expanded the current definition of tobacco products to include synthetic nicotine, that the FDA received authority to regulate synthetic nicotine products.

Regulating individual analogs has the opposite problem of class-wide regulation of analogs. While it allows space for research and innovation around a new analog, it also creates regulatory lag when a novel analog enters the market—making it unclear how and by whom it can be regulated.

Conclusion

Regulating analogs in groups and individually present different challenges for policymakers; however, both can fall into the same trap of erroneously assuming a similar chemical structure implies a similar function. If the goal is to prevent health harms from befalling the public, then a chemical’s function is more important than its physical structure. For this reason, establishing each substance’s effect on the body before taking regulatory action is a vital first step in determining the proper regulatory measures, even if it’s less expedient. Policy is rarely a “set it and forget it” process, and the same is true of substance regulation. Policymakers must be prepared to revisit and revise regulations as markets change.