MDMA Enhances Emotional Empathy and Prosocial Behavior

Cédric M. Hysek; Yasmin Schmid; Linda D. Simmler; Gregor Domes; Markus Heinrichs; Christoph Eisenegger; Katrin H. Preller; Boris B. Quednow; Matthias E. Liechti


Soc Cogn Affect Neurosci. 2014;9(11):1645-1652. 

In This Article

Materials and Methods


Thirty-two healthy subjects (16 men, 16 women) with a mean age of 25 ± 3 years (mean ± s.d.; range 20–31 years) were recruited from the University of Basel campus. Subjects with a personal or first-degree relative history of psychiatric disorders or chronic or acute physical illness were excluded as previously described (Hysek et al., 2012c). Additional exclusion criteria were smoking, a lifetime history of using illicit drugs more than five times, with the exception of past cannabis use, and any illicit drug use including cannabis within the last 2 months or during the study period, determined by repeated urine tests conducted during screening and before each test session using TRIAGE 8 (Biosite, San Diego, CA, USA). Nineteen subjects had used cannabis more than five times in the past. Fifteen participants reported using other illicit drugs one to four times. Most of the subjects (n = 22) were completely MDMA naïve while 10 subjects had less than five previous experiences with MDMA. The use of a within-subjects study design avoided confounding of the acute MDMA effect by drug history in this study. Female subjects were investigated during the follicular phase (Day 2–14) of their menstrual cycle to account for cyclic changes in the reactivity to amphetamines.

Experimental Protocol

We used a double-blind, placebo-controlled, cross-over design where all 32 subjects were treated with both MDMA (125 mg) and placebo (64 assessments). The use of a within-subject design eliminated inter-individual differences and increased the power of the study considerably above that of a parallel design (n > 64). The washout period was at least 10 days. The study was conducted in accordance with the Declaration of Helsinki and International Conference of Harmonization Guidelines in Good Clinical Practice and approved by the local Ethics Committee. The study was registered at (NCT01386177 and NCT01465685). All the subjects provided written informed consent before participating in the study and were paid for their participation.

Study Drug

MDMA (Lipomed AG, Arlesheim, Switzerland) was prepared as gelatin capsules with mannitol as filler. Identical placebo capsules contained only mannitol. MDMA was administered orally at a dose of 125 mg, corresponding to a mean dose of 1.89 ± 0.30 mg/kg body weight (mean ± s.d.).


Subjective Effects. Visual analog scales (VASs) (Hysek et al., 2012b) were repeatedly used to assess subjective effects related to prosociality, including feeling 'happy', 'open' and 'close to others'. In addition, the 60-item Adjective Mood Rating Scale (AMRS) was used to assess subjective mood effects (Janke and Debus, 1978; Hysek et al., 2011).

Multifaceted Empathy Test. The MET was used to assess the cognitive and emotional aspects of empathy (Dziobek et al., 2008; Hurlemann et al., 2010). The test consisted of 40 photographs that showed people in emotionally charged situations (Hurlemann et al., 2010). To assess cognitive empathy, the participants were required to infer the mental state of the subject in each scene and indicate the correct one from a list of four responses. Cognitive empathy was defined as the percentage of correct responses in the total responses. To measure emotional empathy, the subjects were asked to rate how much they were feeling for the individual in each scene (i.e. explicit emotional empathy) and how much they were aroused by each scene (i.e. implicit emotional empathy) on a 1–9 point scale. The latter rating provides an inherent assessment of emotional empathy, which is considered to reduce the likelihood of socially desirable answers (Dziobek et al., 2008). The three aspects of empathy were each tested with 20 stimuli with positive valence and 20 stimuli with negative valence, resulting in a total of 120 trials. The MET was performed 3 h after drug administration and after the initial intense subjective peak drug effects had reached a stable level.

Interpersonal Reactivity. A validated German version (Paulus, 2009) of the interpersonal reactivity index (IRI) (Davis, 1983) was used once to assess trait empathy.

Social Value Orientation Test. The paper-based SVO measure was used to assess social behavior (Murphy et al., 2011). In such a resource allocation task, prosociality is defined as a behavior that maximizes the sum of resources for the self and others and minimizes the difference between the two (Haruno and Frith, 2010; Murphy et al., 2011). The test consists of six primary and nine secondary SVO slider items with a resource allocation choice over a defined continuum of joint payoffs (Murphy et al., 2011). The participants were instructed to choose their allocation that defines their most preferred joint distribution between themselves and another person. Allocated funds had real value, and two randomly selected subjects received the funds they earned.

For the primary items, mean allocations for self and the other were calculated. The inverse tangent of the ratio of these two means then produced an angle that indicated the participants' SVO index. A greater SVO angle indicates that the participant more often chose the option that maximized the allocation for the other person, consistent with prosocial or altruistic behavior. The nine secondary items were used to differentiate between two prosocial motivations, inequality aversion and joint gain maximization. The inequality-aversion index was calculated as previously described (Murphy et al., 2011). An index of 0 indicates perfect inequality aversion, and 1 indicates maximal preference for joint gain maximization. The test was administered after the MET at 4 h after drug administration.

Facial Affect Recognition. Facial affect recognition was tested using a dynamic FERT (Domes et al., 2008) (Supplementary data As dependent variables, the emotional intensity at which the trial was stopped for correct answers was recorded. The emotion recognition accuracy was then assessed, defined as the percentage of correctly identified emotions (Domes et al., 2008). The FERT was performed 2 h after MDMA or placebo administration during the peak effect of MDMA.

Endocrine Measures and Pharmacokinetics of MDMA. Plasma levels of oxytocin and copeptin were determined before and 1 and 2 h and levels of cortisol, prolactin and testosterone before and 2 h after drug administration using different immunoassays (Morgenthaler et al., 2006; Simmler et al., 2011; Neumann et al., 2013) and Supplementary material The concentrations of MDMA were determined repeatedly (Figure 4E) using HPLC-tandem mass spectrometry according to (Hysek et al., 2012a,d).

Statistical Analysis

Repeated measures were expressed as peak changes from baseline (ΔE max). Drug effects were first analyzed by an overall analysis of variance (ANOVA), with drug as a within-subject factor. The modulatory effects of sex were then analyzed by ANOVAs, with drug as within- and sex as between-subjects factors. The effects of trait empathy in the IRI on MDMA-induced changes in state empathy in the MET were analyzed using the IRI scale scores (low vs high median split) as between-subject factor. Tukey post hoc comparisons were based on significant main effects or interactions in the ANOVAs. Order effects were excluded by ANOVAs, with session order as a factor. Confounding effects of previous cannabis use on the sex–drug interaction were excluded by ANOVAs, with drug experience as additional factor. Pearson's correlation coefficients were used to determine associations between measures.