MDMAMDMA

MDMA decreases the effects of simulated social rejection

This placebo-controlled study (n=36) investigated the effects of MDMA (52.5mg & 105mg/70kg) on social rejection, as measured by self-reported ratings of positive mood and self-esteem in response to being excluded during a virtual ball-toss game. MDMA increased subjective pro-social feelings of lovingness, and reduced the impact of simulated social rejection on mood and self-esteem, in a dose-dependent manner.

Authors

  • Harriet de Wit

Published

Pharmacology Biochemistry and Behavior
individual Study

Abstract

Introduction: 3-4-methylenedioxymethamphetamine (MDMA) increases self-reported positive social feelings and decreases the ability to detect social threat in faces, but its effects on experiences of social acceptance and rejection have not been determined. We examined how an acute dose of MDMA affects subjective and autonomic responses to simulated social acceptance and rejection. We predicted that MDMA would decrease subjective responses to rejection. On an exploratory basis, we also examined the effect of MDMA on respiratory sinus arrhythmia (RSA), a measure of parasympathetic cardiac control often thought to index social engagement and emotional regulation.Methods: Over three sessions, healthy adult volunteers with previous MDMA experience (N = 36) received capsules containing placebo, 0.75 or 1.5 mg/kg of MDMA under counter-balanced double-blind conditions. During expected peak drug effect, participants played two rounds of a virtual social simulation task called “Cyberball” during which they experienced acceptance in one round and rejection in the other. During the task we also obtained electrocardiograms (ECGs), from which we calculated RSA. After each round, participants answered questionnaires about their mood and self-esteem.Results: As predicted, MDMA decreased the effect of simulated social rejection on self-reported mood and self-esteem and decreased perceived intensity of rejection, measured as the percent of ball tosses participants reported receiving. Consistent with its sympathomimetic properties, MDMA decreased RSA as compared to placebo.Discussion: Our finding that MDMA decreases perceptions of rejection in simulated social situations extends previous results indicating that MDMA reduces perception of social threat in faces. Together these findings suggest a cognitive mechanism by which MDMA might produce pro-social behavior and feelings and how the drug might function as an adjunct to psychotherapy. These phenomena merit further study in non-simulated social environments.

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Research Summary of 'MDMA decreases the effects of simulated social rejection'

Introduction

Frye and colleagues frame 3,4-methylenedioxymethamphetamine (MDMA) as a recreational drug reputed to enhance social engagement and empathy, and note that controlled studies have documented increases in subjective pro-social feelings and alterations in processing of social cues (for example, reduced amygdala response to angry faces and impaired identification of fearful expressions). They point out a gap in the literature: prior findings largely concern explicit cognitive judgements of facial expressions, while it remains unclear whether MDMA alters responses to more complex, interactive social situations involving perceived acceptance or rejection. To address this gap the investigators tested two linked hypotheses. First, they predicted that acute MDMA administration would attenuate the negative effects of simulated social rejection on mood and self-esteem. Second, on an exploratory basis they examined whether MDMA alters parasympathetic cardiac control — measured as respiratory sinus arrhythmia (RSA), an index of vagal activity often associated with social engagement and emotional regulation — and whether RSA changes were related to MDMA's effects on responses to rejection. The Cyberball ostracism paradigm was selected to present a more complete simulated social situation than simple facial emotion recognition tasks.

Methods

This was a within-subjects, double-blind, counter-balanced study in which healthy adult volunteers with prior MDMA experience (N = 36; 18 female; ages 18–35) completed three 5-hour sessions separated by at least 96 hours. In each session participants received two opaque gelatin capsules containing either placebo (d‑glucose), 0.75 mg/kg MDMA, or 1.5 mg/kg MDMA. Participants were screened with physical exam, ECG, a modified SCID, and drug-use history; inclusion required prior MDMA use between 4 and 40 times and absence of recent major psychiatric disorder, significant medical contraindications, pregnancy, extreme BMI, and other exclusions noted by the study team. Women not on hormonal contraception were scheduled during the follicular menstrual phase. Compliance with abstinence instructions was urine- and breath-test verified. Subjective social-emotion effects were assessed using single-item visual analogue scales (0–100) including a 'Loving' item and the Drug Effects Questionnaire (DEQ) 'Feel High' item; repeated measures were taken at baseline and several post‑dose timepoints (30, 60, 120, 180, 210, 240 minutes). During the expected peak drug effect participants played two rounds of the Cyberball virtual ball‑toss task while ECG was recorded. One round simulated acceptance (participant received ~63% of throws) and one simulated rejection (~30% of throws); order was counterbalanced within session. After each game participants completed mood (6 items, α = 0.77) and self‑esteem (12 items, α = 0.89) questionnaires and estimated the percentage of throws they received (0–100%). Cardiovascular data were recorded in Lead II and processed to derive RSA by spectral analysis of interbeat intervals in the respiratory band (0.12–0.40 Hz); baseline and task-period RSA were averaged across 60-s segments. Due to equipment malfunction cardiovascular sample sizes were smaller (n = 24/36). Analyses used repeated-measures ANOVA with planned contrasts. Subjective measures that violated normality were summarised as area-under-the-curve (AUC) relative to baseline and compared across drug conditions using one-way RMANOVA; post-hoc timepoint tests used Wilcoxon signed-rank tests. Heart-rate AUC was analysed with RMANOVA and timepoint differences by t-test. RSA in the absence of task and during Cyberball were analysed with 3 (drug) × 2 (social condition) RMANOVAs. Session order was tested as a covariate but did not alter results and was omitted for simplicity.

Results

Frye and colleagues confirmed expected subjective and cardiovascular stimulant effects of MDMA. Both MDMA doses produced greater DEQ 'Feel High' and VAS 'Loving' area-under-the-curve scores in a linear dose-dependent fashion (DEQ Feel High: linear dose F[1,34] = 130.5, p < .001; VAS Loving: linear dose F[1,34] = 8.231, p < .01). These effects were present at time points before and after the Cyberball task. Heart rate AUC also increased with MDMA (linear dose F[1,26] = 71.815, p < .001). On the primary social outcomes, MDMA reduced the impact of simulated social rejection on self-reported mood and self-esteem: participants under MDMA showed smaller decreases in mood and self-esteem following the rejection Cyberball round than under placebo, while responses to simulated acceptance were not changed. The high dose of MDMA also altered perceived objectivity of rejection: it increased the percentage of throws participants reported receiving, indicating a reduced perception of being excluded. Exact group means and test statistics for the mood/self‑esteem questionnaire comparisons at individual doses are not fully specified in the extracted text. In psychophysiology findings, the high MDMA dose decreased RSA AUC over the session despite RSA tending to increase over time (linear dose F[1,26] = 9.573, p < .05). Simulated rejection in Cyberball did not affect RSA (social condition F[1,23] = 0.013, p = .910). MDMA decreased RSA measured during Cyberball compared with placebo (linear dose F[1,23] = 29.483, p < .001), and there was no significant interaction between drug and social condition on RSA (linear dose × social condition F[1,23] = 1.602, p = .218). Because Cyberball did not elicit a reliable RSA change, the investigators could not assess MDMA's effect specifically on autonomic responses to rejection. Cardiovascular analyses were based on the reduced subsample (n = 24) due to equipment issues.

Discussion

The investigators interpret their findings as evidence that MDMA produces a pro‑social state by both increasing positive social feelings and reducing sensitivity to negative social cues. Specifically, MDMA increased self‑reported lovingness and attenuated the adverse effects of simulated rejection on mood and self‑esteem, while not amplifying responses to simulated acceptance. They emphasise that MDMA also reduced participants' perceived intensity of rejection, extending prior work showing impaired perception of negative facial expressions to a more interactive social context. Frye and colleagues note that the reduction in rejection effects was larger and occurred at lower doses than the change in perceived rejection, suggesting MDMA may influence social processing through more than simple perceptual impairment. They contrast this pattern with amphetamine, which increases sensitivity to subtle emotional cues. Neurohormonal mechanisms are discussed: although oxytocin has been implicated in MDMA's pro‑social actions, the investigators point out that intranasal oxytocin does not reproduce the Cyberball effects observed here, implying other transmitters such as serotonin and norepinephrine may contribute. The decrease in RSA during MDMA sessions is consistent with its sympathomimetic action and with effects of serotonergic and noradrenergic agents on vagal indices; however, the authors note a paradox because lower vagal activity is typically associated with reduced social engagement whereas MDMA here increased self‑reported social feelings. They therefore caution that RSA may not be a straightforward psychophysiological marker of social orientation under MDMA. Limitations are acknowledged: the Cyberball manipulation did not elicit an RSA change in this mixed‑gender, non‑deceptive, repeated‑measures context, preventing analysis of autonomic responses specifically to rejection; Cyberball is a simulation and may not capture real‑world social rejection; participants consumed the drug alone in the laboratory, whereas naturalistic MDMA use commonly occurs in social settings; and the Cyberball task was administered after the nominal peak drug window in the broader protocol, possibly underestimating effects. The authors recommend further research in more naturalistic or group contexts and using richer social simulations to clarify mechanisms. They conclude by suggesting potential relevance for MDMA‑assisted psychotherapy — namely, reduction of perceived social risk and diminished negative emotional consequences of disclosure — while noting the same pro‑social effects may contribute to recreational use and abuse.

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RESULTS

We analyzed our data using a planned contrast approach to repeated measures analysis of variance (RMANOVA;. Because the distributions of the raw subjective measures at individual time points violated assumptions of normality, we analyzed the subjective drug effects (DEQ Feel High and VAS Loving) by computing areaunder-the-curve scores relative to the participant's baseline for each session. These were distributed normally, and we compared them using a one-way (Drug) RMANOVA. We then conducted post-hoc tests on individual time points using the non-parametric Wilcoxon signed-rank test to determine if they were significantly different across doses. Similarly, relative area-under-the-curve scores were calculated for heart rate and compared using one-way (drug) RMANOVA, but differences at individual time points were analyzed using Student's t-test. Peak drug effect on RSA in the absence of a task was analyzed using a 3 (drug) by 2 (time) RMANOVA. RSA during Cyberball was first averaged across segments and then, as with the responses to the game-specific questionnaire, analyzed using a 3 (drug) by 2 (social condition) RMANOVA. Due to equipment malfunction, sample sizes for the cardiovascular data are smaller than for the subjective measures (n = 24/36). All of our analyses were also performed with session order as a covariate, but since this did not alter the pattern of results, we omit the session covariate here for simplicity's sake.

CONCLUSION

MDMA increased subjective pro-social feelings of lovingness, consistent with previous reports. MDMA also reduced the impact of simulated social rejection on mood and self-esteem without changing responses to simulated acceptance. The high dose of MDMA also decreased the perceived objective level of rejection, i.e. it increased the percentage of throws that participants reported receiving. Because, contrary to previous results, we found no effect of simulated rejection on RSA, we could not evaluate MDMA's effect on autonomic responses to rejection. MDMA did, however, decrease RSA relative to placebo over the course of the whole session, consistent with its sympathomimetic profile. In summary, MDMA reduced both subjective perceptions of and responses to social rejection, increased positive social feelings, and decreased a cardiac index of vagal activity. Our finding that MDMA decreased perceived intensity of rejection extends previous work, which showed that MDMA impairs perception of negative social information in faces, to a simulated social situation. Previous findings indicated that the facilitation of social motivation and engagement under MDMA administration may result from impaired perception of rejection. However, we report here that MDMA reduces the effect of rejection on mood and self-esteem at lower doses and to a greater degree than it affects perception of rejection (defined here as participants' self-reported perception of how many times they were thrown the ball). This suggests that MDMA may affect social processing and behavior in more ways than just impairing perception. These findings merit further investigation into the effects of MDMA on social perception in more naturalistic social settings. We argue that this suggests that the most prominent effect of MDMA on the processing of social information is impairment of the perception of rejection and responses to rejection, rather than an introduction of positivity bias, because we found no effect of MDMA on any of these subjective measures during simulated social acceptance (though our subjective measures were close to their maximum value after social acceptance, neither distribution showed evidence of the truncation that would be expected if a ceiling effect was masking an effect of MDMA). This is in contrast to the effects of the closely related drug amphetamine, which has been found to generally increase sensitivity to subtle emotional content in facial expressions, an important form of social information, regardless of the valence of the emotion, and to specifically increase emotional reactivity to positive images without affecting responses to negative images. However, fMRI studies have shown that MDMA increases activation in the ventral striatum (a component of the reward pathway) during presentation of happy faces, in addition to a larger decrease in activity in the amygdala (which is associated with the identification of noxious stimuli) during presentation of angry faces, indicating that perhaps MDMA has a more subtle effect on the processing of positive social information that we were unable to detect here. Examining this possibility would be another goal of studying MDMA in more natural social settings. These findings also have implications for putative pharmacological mechanisms for MDMA's pro-social effects. Following the demonstration inthat oxytocin blockade in rats results in the elimination of MDMA's pro-social effects, there has been substantial research directed at establishing the extent of that nonapeptide neurohormone's role in MDMA's action. Intranasally-administered oxytocin has been shown to have a variety of effects on social cognition, including decreasing amygdalar activation and subjective anxiety in response to social stress, increasing attentiveness to social cues, and facilitating social memory processes. However, though oxytocin, like MDMA, biases perception of facial expressions towards positive emotions, it does not alter subjective responses to Cyberball on the same set of measures used here. This may indicate an important role for other neurohormones, like norepinephrine and serotonin, in MDMA's pro-social effects. These same neurohormones also likely play a role in our finding that RSA was lower during MDMA administration, consistent with lower activity in the vagus nerve, as selective serotonin and norepinephrine reuptake-inhibiting compounds have been found to reduce RSA, and MDMA has been found to increase release of both hormones. Lowered levels of vagal activity are typically associated with decreased social engagement behavior and less effective emotional regulation. However, we observed that MDMA increased participants' self-reported feelings of lovingness (Fig.) and reduced responses to social rejection. It is therefore possible that under conditions of MDMA administration, vagal activity is not a good psychophysical indicator of psychological orientation towards social engagement or emotional regulation. We further found no effect of the Cyberball simulated social situations on RSA, in contrast to the effect noted in Murray-Close (2011). That study was, however, with an exclusively female subject pool, and gender differences have been reported in RSA response to social stress. Further, in that study participants played the game only once and were deceived into believing that they were playing with other human beings, rather than with a computer, unlike in this study, two differences that might increase emotional responses to the experience of exclusion. Our findings here, then, indicate that, in a non-deceptive, repeated-measures context, social exclusion in Cyberball does not affect RSA in a mixed-gender population. This study has a number of limitations. As noted previously, our simulated rejection manipulation did not elicit any autonomic response, precluding any analysis of the effects of MDMA on autonomic responses to rejection. Additionally, Cyberball is only a simulation of rejection and does not reflect all aspects of social rejection in the real world. Further studies could use more complex simulations, like the "O-Cam" technique reported in. Further, anecdotal reports of MDMA's effects on social feelings and behavior generally come from settings in which the drug is taken with others, while in this and all other laboratory studies so far, participants have taken the drug alone. Our lab has shown) that participants report different subjective effects of alcohol when they consume it in a social group than when they consume it alone. This phenomenon may extend to MDMA, such that laboratory studies like this one in which the drug is consumed alone may miss effects that are an important part of its use and abuse. Thus, a natural extension of this work would be to administer the drug to dyads and examine subjective and autonomic responses. Lastly, since the results presented here were gathered as part of a larger study, the Cyberball task occurred after peak drug effect, which is between 90 and 120 min. Thus, it is possible that this effect could be even stronger if the task were performed during peak drug effect. As is clear from Fig., however, drug effects were still significantly present both before and after the task. Despite these limitations, the findings reported here, taken together, indicate that MDMA induces a drug state that is pro-social in terms of self-report measures and responses to social stimuli, and that one manner in which MDMA induces this state appears to be by impairing perception of negative social information. Some have expressed concern that MDMA might increase negative cognitions), but we did not have findings supporting that effect here. The impairment of the processing of and concomitant decrease in deleterious effects from negative social information could have a role in MDMAassisted psychotherapy, where the drug could be reducing patients' perception of the risk associated with speaking openly about their issues, encouraging them to perceive that their psychotherapist is accepting of them, and reducing any negative effects of difficult psychotherapy sessions on their mood and self-esteem. It may also contribute to abuse of the drug, as pro-social effects are commonly cited by users as part of the motivation to take MDMA. We hope that this study informs research into these mechanisms and guides the development of improved strategies for both MDMA's use as a psychotherapeutic adjunct and for prevention of the drug's abuse.

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