Mind the gap! Addressing unresolved aspects of abuse potential evaluation and scheduling of classic and novel psychedelic drugs

Psychedelic research is advancing rapidly, creating new challenges for drug developers, regulators, and legislators. Most classic psychedelics under clinical investigation are Schedule I controlled substances with high abuse potential and no accepted medical use. These and next-generation psychedelic drug-candidates require scientific and clinical assessment of their abuse and dependence potential before being placed into a lower controlled drug schedule (C-II to C-V). The FDA is likely to conduct the first regulatory assessment of a classic psychedelic and has provided guidance on addressing clinical and regulatory challenges. This review builds on that foundation, discussing areas of abuse and dependence evaluation that remain unclear.

Study at a glance

Abstract

Psychedelic research is progressing at breakneck speed and is creating new challenges for drug developers, regulatory authorities, and legislators. Most “classic” psychedelics undergoing clinical investigation are C-I controlled drugs with perceived high potential for abuse and no medical use. These and next-generation psychedelic drug-candidates require scientific and clinical assessment of their abuse and dependence potential before transitioning into a controlled drug schedule assigned to clinically approved drugs (C-II to C-V). Food and Drug Administration is likely to undertake the first regulatory assessment of a “classic” psychedelic, and it has led in disseminating advice on how to address the clinical and regulatory challenges. We have built on this foundation by discussing areas of abuse and dependence evaluation procedures that remain unclear or have not previously been covered. Psychedelic drug-candidates can be classified into three categories, that is, “classic” (well-known compounds including psilocybin, N,N -dimethyltryptamine and lysergic acid diethylamide) and “novel” psychedelics (e.g., analogues of known psychedelics), and located between them is what we describe as “grey area” psychedelics (e.g., non-hallucinogenic 5-HT 2A agonists). In this review, we set out clear proposals for categorizing psychedelic drug-candidates, describe the development pathway and abuse/dependence testing procedures appropriate to each, and, finally, offer our perspective on how these drugs will be evaluated and scheduled under the auspices of the U.S. Controlled Substances Act. Although we used the United States as a test case, the principles and analyses we used and the screening framework for assessing the abuse potential of psychedelic drug-candidates are universally applicable and can be easily adapted to the regulatory requirements and procedures in other countries.