Psychedelic drug abuse potential assessment research for new drug applications and Controlled Substances Act scheduling

Introduction

Henningfield and colleagues situate the paper in the historical and regulatory context of psychedelic research, emphasising that classic indoleamine psychedelics (for example, LSD and psilocybin) and certain phenethylamines (for example, MDMA) were placed in Schedule I of the US Controlled Substances Act (CSA) during the 1970s. They note that Schedule I status, coupled with international treaty obligations, has had lasting consequences for access to these compounds, for the conduct of basic and clinical research, and for the pathway to develop approved medicines that contain these substances. The introduction highlights that although decades of basic, clinical, and epidemiological research exist for some compounds, many regulatory questions remain unresolved — notably how abuse-potential evidence should be gathered and used to inform New Drug Applications (NDAs), rescheduling decisions under the CSA, product labelling, and post-approval risk mitigation strategies such as REMS (Risk Evaluation and Mitigation Strategies). This paper sets out to review how abuse-potential research applies to psychedelic medicines within the US regulatory framework. The authors examine the components and purpose of the CSA's eight-factor analysis (8FA), summarise FDA guidance on abuse potential (notably the 2017 guidance), discuss practical and scientific impediments posed by Schedule I for research, evaluate the suitability of standard human abuse-potential (HAP) study designs for strongly hallucinogenic compounds, and propose alternative or modified approaches to characterise abuse-related risks. Throughout, the focus is regulatory science: what evidence agencies will likely require, how that evidence might be generated safely and validly, and what the scheduling and REMS implications could be for potential psychedelic drug products.