Discontinuation of medications classified as reuptake inhibitors affects treatment response of MDMA-assisted psychotherapy

A pooled analysis of participants (n=50) in Phase II MDMA-trials for PTSD found that recent tapering off SSRIs may reduce treatment response (CAPS-IV score).


Rationale: MDMA-assisted psychotherapy is under investigation as a novel treatment for posttraumatic stress disorder (PTSD). The primary mechanism of action of MDMA involves the same reuptake transporters targeted by antidepressant medications commonly prescribed for PTSD.

Objectives: Data were pooled from four phase 2 trials of MDMA-assisted psychotherapy. To explore the effect of tapering antidepressant medications, participants who had been randomized to receive active doses of MDMA (75-125 mg) were divided into two groups (taper group (n = 16) or non-taper group (n = 34)).

Methods: Between-group comparisons were made for PTSD and depression symptom severity at the baseline and the primary endpoint, and for peak vital signs across two MDMA sessions.

Results: Demographics, baseline PTSD, and depression severity were similar between the taper and non-taper groups. At the primary endpoint, the non-taper group (mean = 45.7, SD = 27.17) had a significantly (p = 0.009) lower CAPS-IV total scores compared to the taper group (mean = 70.3, SD = 33.60). More participants in the non-taper group (63.6%) no longer met PTSD criteria at the primary endpoint than those in the taper group (25.0%). The non-taper group (mean = 12.7, SD = 10.17) had lower depression symptom severity scores (p = 0.010) compared to the taper group (mean = 22.6, SD = 16.69). There were significant differences between groups in peak systolic blood pressure (p = 0.043) and diastolic blood pressure (p = 0.032).

Conclusions: Recent exposure to antidepressant drugs that target reuptake transporters may reduce treatment response to MDMA-assisted psychotherapy.”

Authors: Allison A. Feduccia, Lisa Jerome, Michael C. Mithoefer & Julie Holland


The analysis looked at those who tapered off reuptake inhibitors (serotonin, also called SSRIs, and others) versus those who didn’t use these before treatment.

There were at least 5 half-lives (wash-out period) between the last administration of the reuptake inhibitor and the session(s) with MDMA (25 days on average).

“Recent prior use and tapering of medications that target monoamine reuptake transporters resulted in blunted therapeutic and physiological responses to MDMA in phase 2 trials. Participants who tapered reuptake inhibitors at the time of study enrollment had significantly higher CAPS scores at the primary endpoint compared to participants who had not recently taken medications in these drug classes. More participants still met PTSD diagnostic criteria in the taper group (75%) compared to the non-taper group (36.4%) at the primary endpoint.

The possible explanations given in the discussion are:

  1. The binding sites for MDMA may still be downregulated
  2. Or other serotonin receptors may be functioning differently
  3. Withdrawal symptoms from coming of reuptake inhibitors (which in itself could be perceived negatively/increase CAPS-IV scores)

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