Michael Mithoefer spent a decade of his early career as a board certified emergency medical physician. He is also certified in internal medicine, and in 1991 he became certified in psychiatry. He has had his own private practice of psychiatry and clinical research in Mount Pleasant since 1995. He is also a holotropic breathwork facilitator, and is certified in levels I and II of Eye Movement Desensitization and Reprocessing, an integrative form of psychotherapy.

On November 2, 2001, Mithoefer (as principal investigator) and his wife Annie (a psychiatric nurse) obtained FDA approval to run a clinical trial in the United States giving MDMA in combination with psychotherapy to treat chronic, treatment-resistant post-traumatic stress disorder in 12 patients. The first experimental session of his phase II clinical trial happened on April 16, 2004, and the last experimental session took place on July 18, 2008. The trial showed MDMA to be a safe and effective adjunct to psychotherapy for the small group of patients included in the study.