This randomised, double-blind, placebo-controlled, between-subjects study (n=39) assessed the effects of MDMA (35mg and 70mg/70kg) or placebo on physiological and subjective responses to a public speaking task under stressful and non-stressful conditions. Contrary to their initial hypothesis of dampening stress reactions, MDMA produced stress-like effects on both physiological (heart rate, blood pressure, cortisol) and subjective (ratings of stress, tension, and insecurity) ratings on both the stress and no-stress sessions.
Rationale
±3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a stimulant-psychedelic drug with unique social effects. It may dampen reactivity to negative social stimuli such as social threat and rejection. Perhaps because of these effects, MDMA has shown promise as a treatment for post-traumatic stress disorder (PTSD). However, the effect of single doses of MDMA on responses to an acute psychosocial stressor has not been tested.
Objectives
In this study, we sought to test the effects of MDMA on responses to stress in healthy adults using a public speaking task. We hypothesized that the drug would reduce responses to the stressful task.
Methods
Volunteers (N = 39) were randomly assigned to receive placebo (N = 13), 0.5 mg/kg MDMA (N = 13), or 1.0 mg/kg MDMA (N = 13) during a stress and a no-stress session. Dependent measures included subjective reports of drug effects and emotional responses to the task, as well as salivary cortisol, heart rate, and blood pressure.
Results
The stress task produced its expected increase in physiological responses (cortisol, heart rate) and subjective ratings of stress in all three groups, and MDMA produced its expected subjective and physiological effects. MDMA alone increased ratings of subjective stress, heart rate, and saliva cortisol concentrations, but contrary to our hypothesis, it did not moderate responses to the Trier Social Stress Test.
Conclusions
Despite its efficacy in PTSD and anxiety, MDMA did not reduce either the subjective or objective responses to stress in this controlled study. The conditions under which MDMA relieves responses to negative events or memories remain to be determined.
Papers cited by this study that are also in Blossom
Baggot, M. J., Coyle, J. R., Siegrist, J. D. et al. · Journal of Psychopharmacology (2015)
Bedi, G., Hyman, D., De Wit, H. · Biological Psychiatry (2010)
Bershad, A. K., Miller, M. A., Baggot, M. J. et al. · Journal of Psychopharmacology (2016)
Bouso, J. C., Doblin, R., Farré, M. et al. · Journal of Psychoactive Drugs (2008)
MDMA (3,4-methylenedioxymethamphetamine) is a stimulant-psychedelic drug noted for prosocial effects such as increased empathy and social closeness. Earlier laboratory studies report that MDMA can reduce behavioural and neural reactivity to negative social stimuli (for example, threatening faces or simulated social rejection), yet the drug also produces physiological changes that resemble a stress response (increased cortisol, heart rate, blood pressure) and is commonly used in socially intense, physiologically challenging settings. These mixed findings leave unresolved whether acute MDMA reduces reactivity to an acute psychosocial stressor or instead augments physiological stress responses. Bershad and colleagues designed the present study to test whether single low doses of MDMA would dampen subjective and physiological responses to a standard psychosocial stressor, the Trier Social Stress Test (TSST), which involves an evaluative public speaking and arithmetic task. They hypothesised that MDMA would reduce negative subjective responses to the TSST (for example, ratings of stress or insecurity) while possibly increasing physiological measures such as cortisol and cardiovascular activity. The study focused on healthy young adults with light to moderate past MDMA experience and compared placebo, 0.5 mg/kg, and 1.0 mg/kg MDMA under double-blind conditions.
The study used a mixed design: within-subjects for task (stress vs no-stress) and between-subjects for drug (placebo, 0.5 mg/kg MDMA, 1.0 mg/kg MDMA). Thirty-nine healthy adults were randomised to one of the three drug groups (N = 13 per group) and completed two 4-hour laboratory sessions one week apart, receiving the same capsule (drug or placebo) on both visits. Sessions were counterbalanced so each participant experienced one TSST session and one non-stress control session. The TSST comprised 10 minutes preparation, a 5-minute job-speech in front of two interviewers and a camera, and an unexpected 5-minute mental arithmetic task. The control session involved talking about a favourite book or movie and a 5-minute game of solitaire. Participants were healthy volunteers aged 18–35 years, with light to moderate prior MDMA use (4–40 lifetime uses), BMI 19–26, at least high-school education, fluent in English, no regular medications and no DSM-IV Axis I disorder in the past year. Women were tested during the follicular phase (days 2–14) to reduce hormonal variability. Screening included psychiatric and medical assessments, ECG and drug/alcohol testing; prior TSST participation was exclusionary. MDMA hydrochloride and placebo capsules were prepared by the investigational pharmacy. Doses were weight-adjusted (0.5 and 1.0 mg/kg) and chosen on safety grounds. Participants took the capsule at 12:40 and completed the task 90 minutes later. Subjective measures included the Drug Effects Questionnaire (DEQ) and visual analogue scales (VAS) for stress, tension and insecurity, administered at baseline and at multiple post-dose time points (60, 85, 115, 145, 175 minutes). Pre-task appraisal and post-task ratings of threat, challenge and performance satisfaction were also obtained. Physiological measures were continuous heart rate (ambulatory ECG), periodic blood pressure, and salivary cortisol sampled at baseline, 60 minutes post-dose, and 10, 20 and 60 minutes after the task. Analyses used mixed ANOVAs: drug (between-subjects), task and time (within-subjects). Cortisol values were natural-log transformed; two outliers with baseline cortisol >2 SD from the mean were excluded. Missing data were deleted listwise. Greenhouse-Geisser correction was applied when sphericity was violated. Post hoc comparisons used Dunnett's tests. Effect sizes are reported as partial eta squared (ɳp2). Statistical significance was set at p < 0.05.
Sample characteristics were similar across groups: most participants were in their 20s (mean 24.1 ± 3.4 years), 44% identified as Caucasian, and the three drug groups did not differ on demographics or drug-use history. Subjective drug effects: the 1.0 mg/kg MDMA dose produced the expected acute subjective stimulant effects. Compared with placebo, 1.0 mg/kg significantly increased ratings of feeling high (drug × time, F(2,150) = 3.8, p < 0.001, ɳp2 = 0.20; peak at 85 min), liking the drug (drug × time, F(2,150) = 2.5, p < 0.01, ɳp2 = 0.14) and feeling the drug (drug × time, F(2,150) = 3.0, p < 0.01, ɳp2 = 0.17) across several post-dose time points. The 0.5 mg/kg dose did not produce these significant effects. Effects of the TSST: across all groups the TSST successfully induced psychosocial stress. Compared with the control task, the TSST increased VAS ratings of stress (task, F(1,35) = 30.5, p < 0.001, ɳp2 = 0.47), tension (F(1,35) = 17.4, p < 0.001, ɳp2 = 0.33) and insecurity (F(1,35) = 18.0, p < 0.001, ɳp2 = 0.34). On appraisal measures participants rated the TSST as more threatening and challenging, and reported lower self-efficacy and less satisfaction with their performance post-task. Physiologically, the TSST increased heart rate (task, F(1,34) = 20.4, p < 0.001, ɳp2 = 0.38), systolic blood pressure (task, F(1,35) = 6.5, p < 0.05, ɳp2 = 0.16), and cortisol (task, F(1,33) = 5.0, p < 0.01, ɳp2 = 0.13), particularly at 10 and 20 minutes post-task versus baseline. Effects of MDMA: contrary to the hypothesis that MDMA would dampen stress responses, MDMA increased several subjective and physiological measures independent of task. The 1.0 mg/kg dose raised ratings of stress (drug, F(2,35) = 3.6, p < 0.05, ɳp2 = 0.17), tension (drug, F(2,35) = 6.0, p < 0.01, ɳp2 = 0.25), and insecurity (drug, F(2,35) = 3.4, p < 0.05, ɳp2 = 0.16) during both the stress and no-stress sessions. Both MDMA doses increased how challenging participants found the tasks (drug, F(2,35) = 4.4, p < 0.05, ɳp2 = 0.20). Physiologically, the higher dose increased blood pressure overall (drug, F(2,35) = 7.4, p < 0.01, ɳp2 = 0.30), and both doses elevated salivary cortisol relative to placebo (drug, F(2,33) = 33.2, p < 0.001, ɳp2 = 0.67; post hoc p < 0.001 for 1.0 mg/kg, p < 0.05 for 0.5 mg/kg across 60–135 min). Importantly, there were no significant task × drug interactions for subjective effects or cardiovascular measures, indicating that MDMA did not moderate the additional response elicited by the TSST. In sum, the TSST produced the expected subjective and physiological stress responses, MDMA produced its expected subjective stimulant effects and increased cortisol and blood pressure, but it did not reduce reactivity to the psychosocial stressor.
Bershad and colleagues interpret their findings as failing to support the idea that single low doses of MDMA dampen acute psychosocial stress in healthy adults. Although prior work shows that MDMA can reduce behavioural and neural responses to negative social stimuli, in this controlled laboratory test MDMA did not attenuate either subjective or objective responses to the TSST. Instead the drug produced stress-like effects: increased ratings of stress, tension and insecurity, and increases in cortisol and blood pressure across both stress and non-stress sessions. The authors discuss several possible reasons for the discrepancy between these results and prior reports of MDMA’s prosocial or stress-dampening effects. Dose may be critical: MDMA increases plasma oxytocin (a hormone linked to prosocial effects) only at higher doses in some studies, and therapeutic MDMA doses used in PTSD trials are higher than those tested here. Context and task characteristics could also matter; the TSST is a particular form of evaluative social stress that may not tap the same processes as tasks showing MDMA-related reductions in negative social perception or as a psychotherapeutic setting in which MDMA has shown promise. Individual differences and sample size are additional concerns: the present sample was modest and not powered to examine sex differences or other moderators. The authors acknowledge limitations including the relatively low doses tested, the small sample size that limits subgroup analyses, and the possibility that the TSST may not be the optimal paradigm to reveal MDMA’s unique social effects. They also note that laboratory settings differ from naturalistic or psychotherapeutic environments where MDMA might have different effects. Finally, Bershad and colleagues highlight that MDMA’s effects are complex and may dissociate anxiety or arousal from changes in social behaviour or memory processing—for example, MDMA can increase anxiety while simultaneously making it easier to discuss emotional memories. They conclude that the conditions under which MDMA reduces responses to negative social stimuli—such as dose, context, participant characteristics, or outcome measures—remain to be determined.
Analyses were conducted using SPSS version 16.0 for Windows. Missing cases (due to equipment malfunction or other data collection problems) were deleted listwise, which led to smaller sample sizes for some analyses. To verify that the two dose groups were matched on demographic information, we compared the groups using a one-way analysis of variance (ANOVA). Drug effects during the no-stress control session provided a measure of the direct effects of the drug and were analyzed using a mixed ANOVA, with time as the within-subjects factor and treatment group (0.5 mg/kg MDMA vs. 1.0 mg/kg MDMA vs. placebo) as the betweensubjects factor. Responses to stress were analyzed using mixed ANOVAs, with task (TSST vs. control) and time as within-subjects factors, and treatment group as the betweensubjects factor. Significant effects were further investigated post hoc Dunnett's tests. The cortisol values were transformed with the natural logarithm function, and two outliers with baseline cortisol levels greater than two standard deviations from the mean were excluded (as described in. Repeated-measures ANOVAs were performed with Greenhouse-Geisser correction where violations of sphericity were observed. Differences were considered to be significant if p < 0.05. Effect sizes are reported using partial eta squared (ɳp 2 ) for analyses of variance: 0.01, 0.06, and 0.14 are considered small, medium, and large effect sizes, respectively.
In this study, we assessed the effects of MDMA (0.5 and 1.0 mg/kg) or placebo on physiological and subjective responses to a stressful public speaking task. Based on evidence that MDMA reduces responses to threatening social stimuli in humans, we hypothesized that these relatively low doses of the drug would decrease reactivity to psychosocial stress. Contrary to our hypothesis, MDMA did not reduce subjective responses to stress and instead produced stresslike effects on both physiological (heart rate, blood pressure, cortisol) and subjective (ratings of stress, tension, and insecurity) ratings on both the stress and no-stress sessions. This is the first laboratory based study to test the acute effect of MDMA on responses to a psychosocial stressor in healthy volunteers. Even though MDMA is known to produce stress-like physiological responses, we hypothesized that MDMA might reduce subjective responses to psychosocial stress. First, many studies have demonstrated that MDMA produces positive, Bprosocial^effects, such as the facilitation of social interaction in humans and other species). We reasoned that these prosocial effects might reduce the negative emotional impact of the public speaking task. Second, MDMA reduces responses to negative social contexts specifically, including subjective, behavioral, psychophysiological, and neural responses to images of threatening facesand emotional responses to social rejection using the Cyberball task). If MDMA dampens the ability to recognize threatening faces, it may reduce how negatively subjects perceive the evaluators during the TSST. Even if the drug makes it more difficult to perform the task, this reduction in response to threat of social evaluation may serve to reduce the perceived stressfulness of the task. Similarly, our previous Cyberball results suggest that MDMA reduces the negative mood experienced in response to acute social rejection. Finally, MDMA has shown promise in the treatment of post-traumatic stress disorder (PTSD;), suggesting that it may reduce anxiety while processing memories of stressful events. Despite these prior findings, MDMA failed to dampen negative mood responses to the TSST. On the other hand, there is a large body of research showing that MDMA exerts physiological effects that resemble the effects of an acute psychosocial stressor, including increasing cortisol. As a stimulant drug, MDMA is known to increase blood pressure and heart rate even in the absence of stress. Consistent with this, MDMA in the present study increased heart rate and blood pressure even during the control session without stress. It has been argued that the effects of MDMA on cortisol levels may contribute to its stimulating effects, particularly in stimulating social settings. We saw no evidence of this in the present study. Subjects did not indicate that they liked the drug more after acute stress, when their cortisol levels were elevated. MDMA can also, like acute social stress, increase ratings of anxiety. Interestingly, in one study, the drug increased ratings of anxiety even while dampening fear of negative social evaluation. Thus, MDMA has some stress-like effects on both physiological and subjective ratings, but these are nuanced and may depend on both the setting and the population. The apparently mixed anxiolytic and anxiogenic effects of MDMA raise many questions. When does the drug alleviate stress responses and when does it worsen them? How does MDMA differ from other stimulant drugs in this respect? Are the effects dependent on dose, or subject sample, or context? Or, does MDMA reduce memories of adverse events without affecting acute responses to adverse events? Previous studies addressing the behavioral and subjective mechanisms of MDMArelated effects have provided some insights into these questions. MDMA may specifically dampen negative memories, as described in a recent report by. This study found that acute doses of MDMA increased self-reported anxiety, but it also paradoxically increased how comfortable participants felt describing emotional memories. This suggests that anxiety and social discomfort are dissociable processes, with distinct underlying mechanisms. Although previous evidence suggests that the drug alters perception of positive or negative social stimuli, it may also independently changes behavioral responses, biasing these responses in a prosocial manner. In this way, it might increase anxiety, while simultaneously altering behavioral responses to the experience of such anxiety. Some of the differences across studies may be related to the doses of MDMA used. MDMA increases plasma levels of oxytocin, and oxytocin itself reduces responses to acute stress. There is some evidence that the prosocial effects of MDMA are mediated by oxytocin. However, MDMA only increases plasma oxytocin levels at higher doses (i.e., 1.5 mg/kg) and 1.1 mg/kg in a single study)), raising the possibility that a stress-dampening effect only occurs at higher doses. Interestingly, the doses used for PTSD therapy are higher than the doses we used in this study. Our doses were selected because of safety concerns about the possible combined effects of MDMA and stress, but higher doses might yield different results. This study has several limitations. First, as just noted, the doses of MDMA were low, and it may be that higher doses of MDMA are needed to dampen the stress response. Furthermore, our sample size was small and not large enough to examine sex differences or other sources of individual differences that might affect responses to MDMA. It is also possible that the TSST was not the optimal task to detect the unique social effects of MDMA, and that the drug's effects might interact with characteristics of the participants in the social interaction (e.g., familiarity, degree of threat, gender). Finally, while we tested participants in a comfortable laboratory setting, the drug may produce different effects in a nonlaboratory setting or in a psychotherapeutic setting. Future studies might address these questions of dosing, oxytocin release, individual differences, and contexts. In conclusion, we found no evidence for a stressdampening effect of MDMA in healthy young adults. Our results were surprising in light of previous evidence of MDMA's ability to dampen responses to threatening social input, and the recent evidence in support of its potential as a treatment, in combination with psychotherapy, for PTSD. It remains to be determined what the conditions are under which the drug dampens responses to negative social stimuli, including contextual conditions (laboratory, natural, or psychotherapeutic), doses, participants, or outcome measures. Compliance with ethical standards
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