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Federal Register / Vol. 86, No. 40 / Wednesday, March 3, 2021 / Proposed Rules
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hazard to their health or to the safety of other individuals or to the community; or b There is significant diversion of the drug or drugs containing such a substance from legitimate drug channels; or c Individuals are taking the drug or drugs containing such a substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs in the course of his professional practice; or d The drug or drugs containing such a substance are new drugs so related in their action to a drug or drugs already listed as having a potential for abuse to make it likely that the drug will have the same potentiality for abuse as such drugs, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community.

The abuse potential of 2-fluoro orthofluorofentanyl, 4-methyl acetyl fentanyl, b-methyl fentanyl, b-phenyl fentanyl, ortho-fluorobutyryl fentanyl, ortho-methyl acetylfentanyl, orthomethyl methoxyacetyl fentanyl, paramethylfentanyl, phenyl fentanyl, and thiofuranyl fentanyl is associated with their pharmacological similarity to other schedule I and II mu-opioid receptor agonist substances, which have a high potential for abuse. Similar to morphine and fentanyl, these 10 substances have been shown to bind and act as muopioid receptor agonists.
These 10 substances have no approved medical use in the United States and have been encountered on the illicit drug market. The use of some fentanyl-related substances has been associated with adverse health outcomes, including death. The appearance of several substances structurally related to fentanyl in the illicit drug market has resulted in a significant increase in drug overdose deaths in the United States. According to the Centers for Disease Control and Prevention CDC overdose death data for 2018, there continues to be an increase in the number of deaths related to synthetic opioids. Opioids were involved in about 70 percent of all druginvolved overdose deaths in 2018.
Further, CDC reports demonstrate that the increase in synthetic opioid overdose deaths are largely attributed to an increase in the supply of illicitly manufactured fentanyl and substances structurally related to fentanyl. Because 2-fluoro ortho-fluorofentanyl, 4-methyl acetyl fentanyl, b-methyl fentanyl, bphenyl fentanyl, ortho-fluorobutyryl fentanyl, ortho-methyl acetylfentanyl, ortho-methyl methoxyacetyl fentanyl, para-methylfentanyl, phenyl fentanyl, and thiofuranyl fentanyl are not Food
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and Drug Administration FDAapproved drug products, a practitioner may not legally prescribe them, and these substances cannot be dispensed to an individual. Therefore, the use of 2fluoro ortho-fluorofentanyl, 4-methyl acetyl fentanyl, b-methyl fentanyl, bphenyl fentanyl, ortho-fluorobutyryl fentanyl, ortho-methyl acetylfentanyl, ortho-methyl methoxyacetyl fentanyl, para-methylfentanyl, phenyl fentanyl, and thiofuranyl fentanyl is without medical advice, and accordingly leads to the conclusion that these 10
substances are abused for their opioidergic properties.
There are no legitimate drug channels for 2-fluoro ortho-fluorofentanyl, 4methyl acetyl fentanyl, b-methyl fentanyl, b-phenyl fentanyl, orthofluorobutyryl fentanyl, ortho-methyl acetylfentanyl, ortho-methyl methoxyacetyl fentanyl, paramethylfentanyl, phenyl fentanyl, and thiofuranyl fentanyl as marketed FDAapproved drug products, but these substances are available for purchase from legitimate chemical companies for research purposes. However, despite the limited legitimate research use of these 10 substances, reports from public health and law enforcement data indicate that all 10 substances are being abused and taken in amounts sufficient to create a hazard to an individuals health. Data from forensic databases can be used as an indicator of illicit activity with drugs and abuse 4 within the United States. According to the National Forensic Laboratory Information System NFLIS,5 which collects and analyzes drug exhibits submitted to Federal, State, and local forensic laboratories, there were 235 total reports of seven of the 10 substances 4-methyl acetyl fentanyl, b-methyl fentanyl, orthofluorobutyryl fentanyl, ortho-methyl acetylfentanyl, para-methylfentanyl, phenyl fentanyl, and thiofuranyl fentanyl between 2017 and 2020
queried on July 16, 2020. In 2017 and 2018, U.S. Customs and Border Protection CBP reported that two other of the 10 substances 2-fluoro orthofluorofentanyl and b-phenyl fentanyl have been positively identified in seized drugs, respectively. In 2018, orthomethyl methoxyacetyl fentanyl was 4 While law enforcement data is not direct evidence of abuse, it can lead to an inference that a drug has been diverted and abused. See 76 FR
77330, 77332, Dec. 12, 2011.
5 NFLIS is a DEA program and a national forensic laboratory reporting system that systematically collects results from drug chemistry analyses conducted by state and local forensic laboratories in the United States. The NFLIS database also contains Federal data from U.S. Customs and Border Protection CBP. NFLIS only includes drug chemistry results from completed analyses.

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positively identified in an exhibit submitted to NMS laboratories for analysis by the Department of Homeland Security. Consequently, the positive identification of the 10
substances in law enforcement encounters indicates that these substances are being abused, and thus pose safety hazards to the health of users.
2. Scientific Evidence of the Drugs Pharmacological Effects, if Known: 2fluoro ortho-fluorofentanyl, 4-methyl acetyl fentanyl, b-methyl fentanyl, bphenyl fentanyl, ortho-fluorobutyryl fentanyl, ortho-methyl acetylfentanyl, ortho-methyl methoxyacetyl fentanyl, para-methylfentanyl, phenyl fentanyl, and thiofuranyl fentanyl are pharmacologically similar to other schedule I and schedule II mu-opioid receptor agonist substances. The abuse potential assessed by drug discriminative studies of 2-fluoro ortho-fluorofentanyl, 4-methyl acetyl fentanyl, b-methyl fentanyl, b-phenyl fentanyl, ortho-fluorobutyryl fentanyl, ortho-methyl acetylfentanyl, orthomethyl methoxyacetyl fentanyl, paramethylfentanyl, phenyl fentanyl, and thiofuranyl fentanyl show that these substances share discriminative stimulus effects similar to fentanyl and morphine. Similar to schedule I and II
opioid analgesics, these 10 substances bind to and activate the mu-opioid receptor. Additionally, behavioral studies in animals demonstrate these 10
substances produce analgesic effects similar to fentanyl and morphine. Pretreatment with naltrexone, an opioid antagonist, attenuated analgesic effect of these 10 substances, as well as fentanyl and morphine. These data indicate that the 10 substances are mu-opioid receptor agonists with effects on the central nervous system. Data from drug discrimination studies showed that these 10 substances share discriminative stimulus effects similar to those of morphine. Thus, it is concluded from in vitro and in vivo pharmacological studies that the effects of the 10
substances are similar to that of fentanyl and morphine and are mediated by muopioid receptor agonism.
3. The State of Current Scientific Knowledge Regarding the Drug or Other Substance: 2-Fluoro orthofluorofentanyl, 4-methyl acetyl fentanyl, b-methyl fentanyl, b-phenyl fentanyl, ortho-fluorobutyryl fentanyl, ortho-methyl acetylfentanyl, orthomethyl methoxyacetyl fentanyl, paramethylfentanyl, phenyl fentanyl, and thiofuranyl fentanyl are synthetic opioids of the 4-anilidopiperidine structural class, which includes fentanyl. As defined in the February 6,
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