MDMA Impairs Both the Encoding and Retrieval of Emotional Recollections

This randomized, double-blind placebo-controlled, between-subjects study (n=60) investigated the effects of MDMA (70mg/70kg) on the retrieval and encoding of emotional memories and found that it diminished both faculties. These results support the notion that MDMA alters the recollection of details associated with emotional events but not memory for the occurrence of the event, which may help patients re-encoding these memories with novel, less emotional associations in the context of therapy.

Abstract

“Introduction: The psychoactive drug ±3,4-methylenedioxymethamphetamine (MDMA) is increasingly used for its perceived emotional effects (eg, prosociality, empathy, psychotherapy), but surprisingly little research has been aimed at identifying the effect of the drug on emotional episodic memory in humans.

Methods: Here, we report the first double-blind placebo-controlled study to examine the effects of MDMA on emotional memory separately during encoding and retrieval in healthy participants. Participants viewed emotionally negative, neutral, and positive pictures and their labels. Forty-eight hours later, they were given cued recollection and recognition memory tests designed to assess recollection and familiarity for the studied pictures. Participants were randomly assigned to one of three groups who received MDMA (1 mg/kg) either during encoding (Encoding group; N=20), retrieval (Retrieval group; N=20), or neither (Placebo group; N=20).

Results: Although MDMA administered at either phase did not affect overall memory accuracy, it did alter the recollection of details associated specifically with emotional memories as estimated using a dual process signal detection analysis of confidence judgments and subjective ‘remember’ judgments. In the Encoding group, MDMA reduced recollection estimates for negative and positive pictures but had little to no effect on neutral items or familiarity estimates. There was evidence for similar trends in the Retrieval group.

Discussion: These findings indicate that MDMA attenuates the encoding and retrieval of salient details from emotional events, consistent with the idea that its potential therapeutic effects for treating posttraumatic stress disorder are related to altering emotional memory.”

Authors: Manoj K. Doss, Jessica Weafer, David A. Gallo & Harriet de Wit

Summary

INTRODUCTION

Recent findings suggest that the stimulant-psychedelic-entactogen MDMA may specifically modulate emotional processing in humans. This is consistent with the characterization of PTSD as a disorder of emotional memory.

MDMA impairs memory for emotionally neutral information, but it can be reversed by blocking the 5-HT2A receptor, a site that binds psychedelic drugs and differentiates MDMA from classic stimulants.

MDMA may have a similar effect on retrieval as dextroamphetamine, but may have a more specific impact on emotional memory representations. This is because MDMA drives the noradrenergic system, which is thought to support emotional memory enhancements.

We sought to disentangle the effects of MDMA on the encoding and retrieval of negative, neutral, and positive memory, as well as on the recollection and familiarity of episodic memories. We predicted that MDMA would attenuate both the encoding and retrieval of emotional memory.

Participants

Sixty healthy participants were recruited, who underwent physical examinations and electrocardiograms, and were screened by trained clinical psychologists using a semistructured psychiatric interview. They were eligible if they reported 4 – 40 past uses of MDMA with no adverse events.

Qualifying participants attended an orientation session to give consent and practice study tasks. They were instructed to abstain from alcohol, prescription drugs, and over-the-counter drugs for 24 h before the sessions, marijuana for 72 h before the sessions, and other illicit drugs for 48 h before the sessions.

Design

Subjects were randomly assigned to one of three groups, and attended two sessions separated by 48 h. All groups received MDMA during encoding and placebo during retrieval.

Stimuli

Stimuli consisted of 180 images from the International Affective Picture Set (IAPS) and 2 – 3 word labels describing these images. The images had mean (SD) normed valences and arousals, respectively.

Procedure

Participants completed compliance measures, a urine drug test, and a pregnancy test, and then consumed a capsule and completed cardiovascular and mood measures every 30 min for the next 90 min.

Participants rated labels and pictures on a 5-point scale, rated the valence and arousal of pictures on a 5 x 5 grid, and self-rated labels and pictures.

Participants were given two surprise memory tests 90 min post-capsule ingestion, a cued recollection test and a picture recognition test. They were instructed to give a ‘remember’ response when they could recollect associated details from the event, and a ‘know’ response when they simply knew it was presented.

Dependent Measures

Several measures were obtained to monitor expected drug effects, including heart rate, blood pressure, mood, and an end of session questionnaire.

For the cued recollection test, hits were calculated and false alarms were subtracted from hits to compute memory accuracy.

To estimate recollection and familiarity, confidence data was submitted to a dual process signal detection (DPSD) analysis using the ROC Toolbox for MATLAB. A receiver operator characteristic (ROC) curve was fitted to these points using maximum likelihood estimation.

Macmillan and Creelman (1991) replaced floor and ceiling hits and false alarms with 0.5/N and 1 – 0.5/N, respectively, to avoid negative familiarity estimates.

Statistical Analysis

The encoding and retrieval groups were compared separately to the Placebo group. ANOVAs were conducted on recollection hits, false alarms, accuracy, and high confidence measures.

We used ROC curves to estimate recollection and familiarity. The main effects of valence were due to the typical advantage for negative stimuli, and the trending main effect of valence on false alarms was due to more false alarms for positive stimuli.

The distributions of DPSD-based recollection and familiarity estimates from the bootstrapping procedure were all normal. The Encoding group had reduced negative and positive recollection estimates compared with the Placebo group.

Recognition: Placebo vs Encoding

The main effect of valence was smaller recollection estimates for positive pictures, and the main effect of group was attenuated recollection in the Encoding group. Valence modulated false alarms, but all other main effects and interactions were not statistically significant.

Although the difference between the Placebo and Retrieval groups was not significant, the difference between the Encoding and Retrieval groups was also not significant. There was also no difference between the Retrieval and Placebo groups for neutral recollection estimates and familiarity estimates.

Recognition: Placebo vs Retrieval

The ANOVA on hits did not reveal any main effects or interactions, but the ANOVA on false alarms did, and the trend for the Retrieval group to false alarm more to positive stimuli than the Placebo group was consistent with the high confidence false alarms on the SOM.

There was a trending main effect of valence on recollection estimates, but no effect of group or interaction. Exploratory contrasts indicated that both negative and positive recollection estimates were reduced compared to neutral estimates in the Retrieval group.

MDMA had subtler effects at retrieval than at encoding, and this effect was strongest on emotional memory. This finding is consistent with previous work demonstrating that MDMA has a stronger effect on emotional memory than other drugs.

MDMA had weak effects on memory retrieval, but did increase false alarms similar to dextroamphetamine. These false alarms were most apparent for positive pictures, especially high confidence false alarms on the cued recollection test (SOM).

MDMA has significant encoding effects on negative information, but amnestic effects on positive information may interfere with its therapeutic value in patients with comorbid depression.

MDMA did not affect the recollection of pictures on the cued recollection test, but did affect the recollection of details associated with emotional events.

MDMA may alter memory for details associated with emotional events but not memory for the occurrence of the event. This may have important clinical implications for preventing generalizations of fear to innocuous stimuli and preventing the incorporation of trauma-related information when thinking about the future.

FUNDING AND DISCLOSURE

HdW has received grants from Pfizer, Indivior, Insys Therapeutics, and Bristol-Myers-Squibb, but no fees were related to the research presented here.