Advancing the Methods to Evaluate Abuse and Dependence-Potential in Clinical Studies for CNS-Active Drugs and Novel Psychedelics
Chairs: Beatrice Setnik, PhD; Jadwiga Martynowicz, PhD
Upcoming Activity: Working Group Meeting, 22nd Annual Scientific Meeting, 18-20 February 2026, Washington DC
Pre-marketing evaluation of abuse and physical dependence potential is a cornerstone of safety assessment and drug scheduling in the United States, consistent with the Controlled Substances Act. The rise of novel CNS-active drug classes (eg. psychedelics) and instances of discordance between abuse potential study outcomes and real-world findings, as observed with dual orexin receptor antagonists, underscore the urgency for ongoing methodological refinement. While many classic psychedelics rely on existing literature and precedent to support scheduling and regulatory decisions at the time of NDA submission, new chemical entities and analogs will require comprehensive human abuse and physical dependence evaluations. The distinct characteristics of psychedelic compounds demand thoughtful adaptations in both study design and choice of endpoints for abuse potential assessments. In addition, the unique psychiatric adverse event profiles of psychedelics warrant consideration of adaptive roles for facilitators or monitors during clinical trials.
For all CNS-active drugs that require physical dependence assessment in phase 3 trials, pragmatic choices regarding endpoint selection and assessment frequency are essential. Methodological concerns, such as the validity of specific withdrawal rating scales for patient populations, adaptation of clinician-rated assessments for patient self-report, and the logistical challenges posed by frequent withdrawal symptom monitoring during discontinuation, remain areas in need of consensus and innovation. These challenges have been discussed amongst the ISCTM working group and as a result two manuscripts have been initiated; one detailing methodological adaptations for physical dependence evaluation of CNS-active drugs, and a second focused on advancing approaches for abuse potential assessment specific to psychedelics and their analogs. This workshop will cover the content and recommendations of these manuscripts prior to journal submission, providing ISCTM members and other attendees with the opportunity to engage with the latest methodological proposals developed by the ISCTM Working Group. Workshop sessions will consist of concise presentations followed by interactive group discussions. The aim is to foster best practices for clinical evaluation of abuse liability and physical dependence, strengthening standards for regulatory review and communication with stakeholders.
Topics to be addressed:
- Evaluating Abuse in Clinical Settings Amid the Emergence of Psychedelic Drugs: Challenges and Proposed Solutions
- Critical Examination of Approaches for Assessing Physical Withdrawal in Phase 3 studies: Best Practices and Ongoing Challenges
ISCTM members are encouraged to participate and learn about these methodological advancements, contributing to the ongoing evolution of clinical standards in abuse and dependence evaluations.
Most Recent Activity:
Poster Presentations at ASCP, May 2025:
Navigating the Unchartered Territory of Assessing Psychedelics in Human Abuse Potential Studies
Working Group Meeting, 21st Annual Scientific Meeting, 19-21 February 2025, Washington DC – View slides
INAUGURAL MEETING: 20th Annual Scientific Meeting, 21-23 February 2024, Washington DC – View summary, View slides
The pre-marketing evaluation of abuse and dependence potential of CNS-active drugs is an integral part of safety assessment and drug scheduling in the US, as per the Controlled Substances Act. Development of new classes of drugs with unique pharmacological attributes (i.e., psychedelics) for targeted medical use and occasional cases of discordant findings between pre-marketing abuse potential studies and real-world data, as seen with dual orexin receptor antagonists, give rise to the need to further examine methodological approaches. While most classic psychedelics will likely rely on the literature to support scheduling decisions at the time of NDA submission, new chemical entities and derivatives may require a full abuse and potential dependence evaluation. The unique pharmacology of psychedelic drugs presents the need for study design adaptation and consideration of appropriate study endpoints for human abuse potential evaluation. This workshop will focus on the key points raised during the recent meeting of the Cross-Company Abuse Liability Council and the FDA Controlled Substance Staff that warrant further discussion amongst the scientific community. The workshop will be structured to share brief presentations followed by group discussions on each topic. The goals of this working group are to continue contributing and outlining best practices in the evolving area of clinical abuse and dependence evaluation that can be shared with stakeholders and regulatory agencies.