Project Summary/Abstract Impaired social motivation, or “asociality,” is a negative symptom of schizophrenia and a cause of significant functional impairment in the illness. Whereas many symptoms of schizophrenia can be treated with antipsychotic medications, deficits in social motivation persist, leading to significant social disability in patients. There is currently no effective treatment for this symptom of the illness. One promising and unexplored avenue to enhance social motivation in schizophrenia is ± 3,4-methylenedioxymethamphetamine (MDMA). MDMA is a psychostimulant that shares some pharmacological properties with amphetamines, but in addition, has pronounced pro-social effects, increasing the motivation to engage socially. In healthy volunteers, it produces feelings of empathy and closeness with others and increases attention to positive social cues, perhaps partly through its effects on the social bonding hormone, oxytocin. MDMA has shown promise in other psychiatric conditions such as PTSD. Thus, MDMA could offer a unique therapeutic benefit in patients with schizophrenia who suffer from impaired social motivation. We plan to test the hypothesis that MDMA enhances social motivation in patients with schizophrenia by conducting a two-phase study. The first phase (Aim 1) will be an open-label, ascending-dose, within-subject trial in which participants will receive 40mg, 80mg, or 120mg of MDMA. The doses will be administered in ascending order, but doses will be stopped if subjects experience moderate or greater psychotic symptoms at 24 hours. This trial will assess the tolerability of the drug in this population and guide in the selection of a maximum well-tolerated dose for the second phase. The primary tolerability measure will be clinician-rated psychotic symptoms (disorganized speech, delusions, hallucinations) collected at 24 hours after MDMA administration. Phase 2 (Aim 2) will be a randomized, placebo-controlled trial using a crossover design to test the acute effects of MDMA on social motivation and plasma oxytocin in patients with schizophrenia. Social motivation will be assessed using a social attention bias task (ABT), which has been validated in MDMA trials with healthy volunteers, in addition to secondary behavioral and self-report measures of social motivation. The results of this project will lay the foundation for further investigations of MDMA and other psychoactive compounds as a treatment for debilitating and difficult-to-treat social deficits in schizophrenia. Future studies will examine interactions between the effects of psychoactive compounds and nonpharmacologic psychosocial interventions targeting social symptoms.

Project Narrative The goal of this project is to test the prosocial compound ± 3,4-methylenedioxymethamphetamine (MDMA) as a novel treatment for a debilitating symptom of schizophrenia, impaired social motivation. This project will proceed in two phases; the aim of Phase 1 will be to establish the tolerability of MDMA in this patient population, and the aim of Phase 2 will be to test the effects of MDMA on social motivation. Results from these studies will be foundational in identifying effective psychopharmacologic and combined psychopharmacologic- psychosocial therapies for social deficits in schizophrenia.