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).

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

“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

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

β take: This article has been retracted (Aug '24). The main reason is that it includes data from at least one patient who had been abused by an (unlicenced) therapist in the MAPS' sponsored Phase II trial. In a reaction to the retraction, the authors argue that excluding the data wouldn't change the headline findings (they have appealed to retraction).

This article was one of the first to argue that those who used SSRIs (antidepressants), and who stopped using them before the trial, would have a blunted response to MDMA-assisted therapy.

MDMA-assisted psychotherapy is under investigation as a novel treatment for posttraumatic stress disorder.

PTSD is a common disorder that affects 3 to 4% of the global population. It can affect multiple areas of life and is associated with an increased risk of suicidal thoughts or behaviour.

Six phase 2 randomized, double-blind placebo-controlled clinical trials were conducted to investigate MDMA-assisted psychotherapy for PTSD treatment. The results showed that participants receiving active doses of MDMA had significant reductions in symptoms of PTSD as measured via Clinician-Administered PTSD Scale for DSM IV (CAPS-IV).

MDMA increases serotonin, norepinephrine, and dopamine by reversing the flow of neurotransmitter through membrane-bound transporter proteins. When MDMA is co-administered with a reuptake inhibitor, the subjective and psychological effects are markedly attenuated.

SSRIs block re-uptake of neurotransmitters back into terminals, which results in decreased negative feedback and ultimately more 5-HT released into the synapse. SSRIs also affect several other neurotransmitters indirectly, including GABA, dopamine, glutamate, and noradrenaline.

The authors pooled data from four phase 2 studies that included both the CAPS-IV and the Beck Depression Inventory-II to understand whether or not having recently tapered off a medication targeting the same primary binding sites as MDMA would affect treatment response.

Methods & Materials