2. Academic Validation
  3. R-MDDMA is a Safer Analogue of MDMA with Therapeutic Potential

R-MDDMA is a Safer Analogue of MDMA with Therapeutic Potential

  • ACS Chem Neurosci. 2026 May 6;17(9):1670-1682. doi: 10.1021/acschemneuro.5c00891.
Maxemiliano V Vargas 1 2,  Cassandra J Hatzipantelis 1 3 4,  Lee E Dunlap 1 5,  Robert J Tombari 1 5,  Arabo A Avanes 1 6,  Sam Vaillancourt 7 8,  Pierre Llorach 7 8,  Juliana S Salgado 7,  Boris D Heifets 7 8,  David E Olson 1 3 4 9
Affiliations

Affiliations

  • 1 Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, California 95616, United States.
  • 2 Neuroscience Graduate Program, University of California, Davis, Davis, California 95618, United States.
  • 3 Department of Chemistry, University of California, Davis, Davis, California 95616, United States.
  • 4 Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California 95817, United States.
  • 5 Chemistry and Chemical Biology Graduate Program, University of California, Davis, Davis, California 95616, United States.
  • 6 Biochemistry, Molecular, Cellular, and Developmental Biology Graduate Program, University of California, Davis, Davis, California 95616, United States.
  • 7 Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California 94305, United States.
  • 8 Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, United States.
  • 9 Center for Neuroscience, University of California, Davis, Davis, California 95618, United States.
PMID: 42010927 DOI: 10.1021/acschemneuro.5c00891
Abstract

Recent clinical evidence suggests that racemic 3,4-methylenedioxymethamphetamine (MDMA) might be useful for treating a range of neuropsychiatric diseases including post-traumatic stress disorder (PTSD) and depression. However, concerns about its abuse potential stemming from its monoamine releasing properties have hampered its clinical development. Thus, safer analogues of racemic MDMA with comparable therapeutic effects are highly desirable. Here, we compare the pharmacological effects of MDMA enantiomers with those of its methylated analogue 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA). We found that R-MDDMA did not directly activate 5-HT2B receptors, induce serotonin efflux, produce a head-twitch response, impact body temperature, or induce hyperlocomotion at therapeutically relevant doses. However, it still promoted structural neuroplasticity in cortical neurons, facilitated fear extinction learning, and produced sustained antidepressant-like effects. Taken together, our results suggest that R-MDDMA might be a safer MDMA analogue with similar therapeutic properties.

Keywords

MDDMA; MDMA; PTSD; depression; entactogen; psychedelic; psychoplastogen.

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