No Signs of MDMA-Related Histopathological Changes to CNS in Rats and Dogs in A 28-Day Repeated Oral Dose Neurotoxicity Study

This study was funded by Multidisciplinary Association for Psychedelic Studies (MAPS) and organized by MAPS Public Benefit Corporation (PBC). 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy is being investigated as a potential treatment option for patients with posttraumatic stress disorder (PTSD). Previous animal MDMA neurotoxicity studies have produced equivocal results, using models with poor face and construct validity. This 28-day study investigated the neurotoxic effects of high-dose MDMA orally administered singly and repeatedly (weekly, 4 total doses) to Sprague-Dawley rats and beagle dogs. Animals received either vehicle (deionized water) or MDMA (rats: 20 or 25 mg/kg [n=10 per sex]; dogs: 9 or 12 mg/kg [n=3 per sex]) via oral gavage. In rats receiving MDMA (25 mg/kg), there were 6 unscheduled mortalities in the male repeated-dose group on Days 2 (n=2) and 16 (n=4). As a result, the MDMA dose for males was reduced to 20 mg/kg on Day 22. In dogs receiving MDMA (12 mg/kg), there were four instances of moribundity and early termination (both sexes) in the single-dose group, and the dose was subsequently decreased to 9 mg/kg for the repeat-dose group. Microscopic examination and expanded neurohistopathology analyses were completed on central nervous system (CNS) tissue on Days 2 (single-dose group) and 29 (repeated-dose group) after the initial dose. Despite mortality or moribundity observed in both species, there were no lesions or substantial neuropathological changes in the CNS tissue of any rats or dogs after a single dose or repeated administration of MDMA. These findings indicated that MDMA did not result in permanent structural damage to the CNS in two distinct animal species following a high dosing schedule.