The "Save Americans from the Fentanyl Emergency Act," or "SAFE Act," aims to address the proliferation of fentanyl-related substances by permanently placing them into Schedule I of the Controlled Substances Act (CSA). This class scheduling applies to any substance structurally related to fentanyl by specific chemical modifications, unless already controlled or explicitly listed elsewhere. The Attorney General is required to publish a list of these substances, though their absence from the list does not negate their controlled status. A significant provision of the bill is that these newly scheduled fentanyl-related substances will not be subject to quantity-based mandatory minimum penalties for domestic or import/export offenses, unlike fentanyl itself and other fentanyl analogues. The bill also establishes a process for the Secretary of Health and Human Services to scientifically evaluate and recommend the removal or rescheduling of a fentanyl-related substance if its potential for abuse is determined to be lower than Schedule V or Schedule I/II substances. This scientific determination would be binding on the Attorney General, who must then act within 90 days. To facilitate scientific understanding, the SAFE Act significantly streamlines the process for conducting research with Schedule I controlled substances. It creates an expedited registration process for practitioners, allowing those already registered for Schedule I or II research to begin new Schedule I research after a 30-day notice, and requiring the Attorney General to register new researchers within 45 days. The bill also permits a single registration for multiple research sites within the same locality and allows agents or employees to work under a registered researcher without separate registration, provided certain conditions are met. Furthermore, it allows researchers to perform small-quantity manufacturing activities for research purposes without needing a separate manufacturing registration, excluding the cultivation of marijuana. The legislation includes a provision for retroactive relief, allowing sentencing courts to vacate or reduce sentences for individuals convicted of offenses involving fentanyl-related substances that are later removed from Schedule I(e) or rescheduled to a less restrictive category. Finally, the bill mandates a Government Accountability Office (GAO) report within four years to analyze the implementation and impact of this permanent class scheduling, including its effects on research, illicit activities, sentencing, and overall efficacy.