INTRODUCTION: Abuse potential assessment of drugs with central nervous system activity is a critical component of the development of new medications for regulatory filings for approval worldwide. These new drug applications typically include recommendations for scheduling status as a controlled substance, if scheduling is warranted. This commentary focuses on the approach and current issues related to scheduling in the United States (US) Controlled Substances Act (CSA); however, scheduling more globally generally involves similar approaches and issues. Although scheduling is intended to protect public health and safety by adequate restrictive control based on the abuse potential assessment, it is also intended to serve medicinal use and access and to incentivize the development of new medicines with reduced abuse-related risks. Thus, overly restrictive scheduling can present risks to public health, as does under-scheduling.
OBJECTIVE: Identify the categories of substances and new drugs that appear most challenging for reliable and valid abuse potential assessment by the widely used abuse potential assessment approaches recommended in the U.S. Food and Drug Administration (FDA) 2017 Guidance and which generally serve globally.
METHODOLOGY: A panel of abuse potential assessment experts convened at a scientific meeting that included many leading abuse potential and regulatory experts, namely the International Study Group Investigating Drugs as Reinforcers. The focus of the panel was novel and psychedelic substances and cannabinoids that raise challenges for accurate abuse potential assessment, in which postmarketing evaluations by the FDA suggested were overestimates of their abuse potential that resulted in overly restrictive scheduling.
RESULTS: There is agreement that many novel acting substances, including medications for treating disorders related to anxiety, sleep, depression, and pain, and including orexin receptor acting substances, psychedelics, and diverse cannabinoids, may require modifications of existing methods and alternative approaches to more fully and accurately characterize their abuse potential and guide CSA scheduling. This included a human abuse potential (HAP) assessment that can raise challenges for the identification of the most appropriate placebo and positive comparators, study populations, and protocols to ensure both safety and scientific reliability.
CONCLUSIONS: The core abuse potential methods that serve U.S. CSA scheduling and global new drug scheduling are generally reliable for many categories of drugs but need to be modified and perhaps supplemented with additional outcome measures to more fully and accurately characterize potential abuse-related risks. This may include behavioral economic assessments in preclinical and clinical studies and a broader range of outcome measures in HAP studies and adverse event assessment in all clinical studies in drug development programs.
