Accelerating Solutions to Understand the Potential of Fast-Acting Psychotomimetic Agents

Presenter

Jonathan Sabbagh, Ph.D.
Division of Translational Research

Goal

The goal of this concept is to support research that addresses the optimization, effectiveness, implementation, coordination, and sustainability of empirically-supported therapeutic and services interventions within and across care settings to better meet the mental health needs of older adults with serious mental illness (SMI).

Rationale

Clinical trials evaluating psychedelics and other psychotomimetic agents, typically in combination with psychotherapy, have demonstrated promising benefits for a range of mental illnesses including depression and post-traumatic stress disorder (PTSD). These compounds, such as psilocybin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (MDMA), hold the potential to provide rapid and long-lasting symptomatic relief following even a single administration. However, these agents also present several challenges to interpreting the data from trials: the pronounced subjective effects observed at higher doses make it difficult to adequately blind studies, there is no agreed upon placebo control for psychedelic trials, psychotherapy is not uniformly implemented across studies, and the enthusiasm surrounding these drugs creates an expectancy effect in trial participants. To better understand the therapeutic potential of these agents and increase confidence in clinical trial results, rigorous studies are needed to identify the key components mediating their sustained beneficial effects.

Furthermore, the cellular/molecular and circuit mechanisms that underlie the therapeutic effects are poorly understood and require additional investigation. Developing a better understanding of the mechanisms responsible for these effects could lead to novel drug development efforts and identification of objective biological markers to assess drug effects. Identifying a pharmacodynamic brain marker would increase confidence in clinical trial results and enhance the rigor of the studies.

Major questions that may be addressed by this concept include, but are not limited to:

• How can clinical trial designs be optimized to overcome the unique challenges associated with psychotomimetic agents?
• What translatable pharmacodynamic brain markers can be identified and developed as more objective measures of drug effects?
• How can we better understand the role of psychotherapy and psychotomimetic effects in the potential efficacy of these agents?