NOVEL THERAPEUTICS WITH ENTACTOGENIC EFFECTS - A NEW FRONTIER FOR MOOD AND ANXIETY DISORDERS?

This panel will offer an overview of novel entactogenic compounds with potential therapeutic application in mood and anxiety disorders and a platform to discuss assessment of entactogenic outcomes. Entactogens are compounds that enhance prosocial behavior and empathy without necessarily possessing hallucinogenic properties. Empathy in psychiatric illness is a complex and understudied construct, hindered by heterogeneous definitions and limited objective tools. To ground the relevance of entactogenic mechanisms in clinical populations, the panel will begin by describing proposed components of empathy: perception of self and others, emotion regulation, social reward processing, and reinforcement of prosocial behavior through learning. The first presenter will discuss EMP01, a novel R-MDMA derivative in development to retain the prosocial effects of racemic MDMA—the “prototype” entactogen—while minimizing adverse physiologic effects. The presentation will review mechanistic and clinical data on EMP-01 as a treatment for Social Anxiety Disorder (SAD). This discussion will highlight the rationale for entactogens as candidate treatments targeting heightened social threat sensitivity, reduced social reward, and impaired learning in SAD. The next two presentations will describe the effect of repeated doses of intravenous ketamine on subjective symptoms related to social reward. Though not traditionally considered an entactogen, the entactogenic properties of ketamine were recently demonstrated through a reverse translational study (Hess et al., 2024). The second panelist will summarize ketamine’s reported entactogenic effects in the literature, then present new data showing that repeated doses of open-label intravenous ketamine reduce social anhedonia in individuals with treatment-resistant depression (TRD) and suicidal thoughts. The third presenter will report ketamine’s effect on subjective loneliness from a randomized midazolam-controlled trial in a cohort of individuals with treatment-resistant bipolar depression (TRBD). Both groups displayed decreases in loneliness over time. The magnitude of change was comparable mid-point, although greater in the ketamine arm only at endpoint, suggesting possible delayed effects. While exploratory, these studies suggest ketamine may influence social reward processing and alleviate subjective social disconnection—core but underappreciated features of mood disorders. The second and third presenters will conclude by discussing potential pharmacological mechanisms underlying ketamine’s entactogenic effects and their therapeutic potential in mood disorders. The final presenter will share results from a pilot study in healthy volunteers using a prosocial learning task, which showed that prosocial learning rates to benefit others (but not oneself) correlated with positive mood during the task, suggesting a link between mood, empathy, and reinforcement. Presenter will outline future directions examining this paradigm in patients with depression and suicidal ideation pre/post-ketamine, and to close, elaborate on the importance of multimodal outcomes (self-report, behavioral, neuroimaging, biomarkers) to assess entactogenic effects. This panel synthesizes emerging work on entactogenic therapeutics and the development of measurable empathy-related constructs as transdiagnostic markers of social impairment. Broader topics—such as how entactogens differ from “empathogens” and psychedelics, designs for future mechanistic trials, and applications to other psychiatric disorders—will also be addressed through discussion.

Learning Objective 1: Describe the neurobiological and clinical rationale for entactogenic compounds—such as EMP-01 and ketamine—as emerging treatments targeting social impairments in mood and anxiety disorders

Learning Objective 2: Evaluate multimodal approaches (e.g., behavioral tasks, neuroimaging, biomarkers) for assessing empathy, social anhedonia, and prosocial learning as transdiagnostic treatment targets in psychiatric populations.

References

• Hess EM, Greenstein DK, Hutchinson OL, et al. Entactogen Effects of Ketamine: A Reverse-Translational Study. Am J Psychiatry. 2024;181(9):815-823. • Stocker K, Liechti ME. Methylenedioxymethamphetamine is a connectogen with empathogenic, entactogenic, and still further connective properties: It is time to reconcile “the great entactogen-empathogen debate.” J Psychopharmacol. 2024;38(8):685-689.