After enrollment, subjects were randomized, in double-blind fashion, to receive two experimental sessions of either psychotherapy with concomitant MDMA administration or the same psychotherapy accompanied by inactive placebo (lactose) administration (psychotherapy-only). The blind was broken for each subject after the follow-up visit 2 months after the second experimental session. All subjects who initially received placebo were offered participation in an open-label crossover segment (‘Stage 2’) (Figure 2). After the 2-month follow-up, nine subjects were given a third session of MDMA with psychotherapy, as allowed in a protocol amendment. However, because not all subjects received a third session and placebo subjects received only two sessions, data related to the third session were omitted from analysis, and for simplicity are omitted from Figure 2.

Study Visits.

Subjects were required to taper and abstain from all psychotropic medication during study participation except sedative hypnotics or anxiolytics used as-needed between MDMA or placebo sessions (referred to as ‘rescue medications’). After preliminary evidence of safety and efficacy had been established, a protocol amendment was approved allowing the last nine subjects to receive a supplemental dose of MDMA or placebo in all experimental sessions. The purpose of this supplemental dose, half the initial dose administered 2 h afterwards, was to prolong the therapeutic window of MDMA effects and gather pilot data about dose for design of future clinical trials.