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

“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

Notes

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)

Summary

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

Introduction

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 behavior.

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.

We 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.

Setting

Four randomized, double-blind trials were conducted at different study sites in the USA, Canada, and Israel. Two early phase 2 trials did not include the BDI-II, and therefore are not included in this analysis.

Participants and study design

Participants with chronic PTSD were enrolled, and psychiatric medications were tapered and discontinued prior to commencing experimental sessions. Anxiolytics and sedative hypnotics were used as needed between experimental sessions, and stimulants for attention deficit disorder were permitted, but had to be discontinued five half-lives prior to each MDMA session.

Participants were randomized to receive either active doses of MDMA (75 – 125 mg) or a control dose (0 – 40 mg MDMA) during psychotherapy sessions with a male/female co-therapy team. The primary outcome measure was the CAPS-IV.

Assessments

The CAPS-IV is a semi-structured interview that consists of three sections: re-experiencing, avoidance, and hyperarousal. It has a dichotomous diagnostic score for meeting PTSD diagnostic criteria.

Statistical analysis

Data were pooled across four studies that used the CAPS-IV and BDI-II and missing data was not imputed.

Participants were divided into two groups for exploratory analyses. The taper group had tapered off medications classified as reuptake inhibitors at the time of screening or enrollment prior to commencing blinded sessions, and the non-taper group had not tapered off medications from this drug class.

Sample

16 out of 50 participants tapered off one drug, and 34 out of 50 participants tapered off two drugs or three drugs. The average number of days from when the medications were stopped to the first MDMA session was 25.1 days.

Nine participants were female in the taper group, and 15 were female in the non-taper group. Both groups were majority White/Caucasian.

Outcome measures–CAPS-IV and BDI-II

The non-taper group had significantly lower CAPS-IV total scores at the primary endpoint than the taper group (p = 0.009), and more participants in the non-taper group did not meet PTSD criteria than those in the taper group (p = 0.011).

There was a significant time – group interaction for BDI-II total scores, with the non-taper group having lower depression symptom severity at the primary endpoint.

Vital signs

For vital sign values across the two blinded sessions, the non-taper group had higher maximum blood pressure values than the taper group, and the number of days abstinent from reuptake inhibitors prior to the first MDMA positively correlated with average maximum body temperature.

Discussion

Recent use and tapering of medications that target monoamine reuptake transporters resulted in blunted therapeutic and physiological responses to MDMA in phase 2 trials. The binding sites (SERT, NET, DAT) for MDMA may have still been downregulated in individuals who tapered reuptake inhibitor medications at the time of study enrollment. Patients can experience withdrawal symptoms for weeks to months after cessation of drugs in this class.

In addition to SERT, other serotonin receptors important for modulating the effects of MDMA may have been functioning differently after chronic use of these medications. These changes could have contributed to the subjective effects of MDMA. In the MDMA-assisted psychotherapy trials, participants were required to have tapered off psychiatric medications at least five drug half-lives prior to starting the blinded sessions, but there was no significant relationship between days of abstinence and PTSD symptom severity.

MDMA binding to transporter proteins reduced peak systolic and diastolic blood pressure and heart rate in the taper group, but not body temperature. This may be due to blunted efflux of serotonin after MDMA administration.

The reduced response to MDMA-assisted psychotherapy in the taper group may have been due to withdrawal symptoms and discontinuation syndrome after cessation of medications. However, baseline depression and PTSD severity scores were equivalent between the taper and non-taper groups, suggesting that withdrawal symptoms were not responsible for the differences in outcome between groups.

One participant failed to respond to MDMA-assisted psychotherapy for social anxiety in autistic adults, but a plasma sample taken during the experimental session confirmed that MDMA had been ingested.

Limitations

The sample sizes were small and data were pooled across four similar studies at different sites. The length of each medication taper was not available, and it is possible that the taper group had a more severe burden of PTSD than the non-taper group.

Conclusions

Participants who discontinued reuptake inhibitor antidepressant medications had less positive outcomes with MDMA-assisted psychotherapy compared to those who had not recently taken these medications.