MDMA was synthesized in 1912 and patented in Germany by Merck in 1914 but was not the subject of human research at that time. In the 1950s it was briefly researched by the U.S. Government as part of the CIA's and the Army's chemical warfare investigations. It was forgotten until the middle 1970s when it was rediscovered by the psychedelic therapy community and began to be used as an adjunct to psychotherapy by psychiatrists and therapists who were familiar with the field of psychedelic psychotherapy. MAPS published a book, The Secret Chief, about the leader of this therapy community.

In the early 1980s, the drug began to be used non-medically, particularly in Texas, under the name Ecstasy. Both the non-medical and therapeutic use of MDMA were made illegal in 1985 despite the Drug Enforcement Administration Administrative Law Judge Francis Young's recommendation that physicians be permitted to continue to administer it to their patients. Rick Doblin, Alise Agar and Debby Harlow helped coordinate the pro-MDMA contingent in the DEA lawsuit. For an excellent history of the early use of MDMA, see Pursuit of Ecstasy by Beck and Rosenbaum.

In 1986, with the goal of developing MDMA's therapeutic potential through FDA-approved protocols, a non-profit organization opened a Drug Master File for MDMA with data gathered from the standard preclinical animal toxicity studies required by FDA. Five different applications for permission to conduct research with MDMA were submitted to FDA between 1986 to 1988, to the Neuropharmacologic Drug Products Division directed by Dr. Paul Leber. All five applications were rejected. Three protocols for double-blind controlled trials were from researchers at, respectively, Harvard Medical School, UC San Francisco Medical School, and U. of New Mexico Medical School, and were all rejected. Two applications submitted by individual physicians were for single case studies, one for a terminal cancer patient who had been successfully treated for pain with MDMA-assisted psychotherapy prior to the criminalization of MDMA and the other for a unipolar depression patient for whom all available treatments had been attempted without success. Both of these single-patient INDs were also rejected. The FDA based its rationale for rejecting all protocols and single case studies on the hypothetical risk of functional consequences of potential neurotoxicity from MDMA Proponents of MDMA research claimed that the rejection of all efforts to conduct FDA-approved MDMA research was based not on rational risk/benefit assessments but on an underlying cultural prejudice against medical research with drugs that were criminalized and on one or more FDA officials' personal opposition to human research with psychedelics. Since FDA Review Divisions are sometimes described as operating like fiefdoms under the control of their Directors, proponents felt profoundly stymied. Proponents claimed that concerns about MDMA neurotoxicity, which numerous studies had failed to link with functional or behavioral consequence and which in any case had not been clearly demonstrated to occur at all at therapeutic does levels, were reminiscent of scientific research in the 1960s that claimed to prove that LSD damaged chromosomes. These reports were effective in generating public disapproval of LSD and in hindering research but were later determined to have no clinically significant effect.

In 1992, FDA reviewed a MAPS-supported protocol submitted by Dr. Charles Grob, then at UC Irvine, for a study of the use of MDMA in the treatment of pain, anxiety and depression in cancer patients. FDA's Drug Abuse Advisory Committee recommended that the cancer patient study be postponed and that a Phase 1 dose-response safety study be conducted first. The protocol was redesigned, with FDA giving final approval for the Phase 1 safety study on November 5, 1992. The safety study was completed in 1995. Data from the safety study revealed no unusual risks and indicated that MDMA could be safely administered within a clinical research context. Dr. Grob submitted the first draft of the protocol for the study of cancer patients in 1997. Negotiations with FDA moved very slowly, due to initial FDA decisions to put MDMA psychotherapy research on a slow track to nowhere. However, FDA opposition eventually lessened as MAPS and Dr. Grob persisted in our efforts to obtain permission for research into the use of MDMA-assisted psychotherapy in cancer patients.