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

Disclosures

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

In This Article

Discussion

The novel findings of this study are that MDMA increased emotional empathy and prosocial behavior. This effect was observed primarily in men. Consequently, male subjects showed more empathic concern and less competitive behavior and exhibited a more prosocial orientation after MDMA treatment, equal to that observed in women with placebo. In addition, MDMA tended to increase the preference for fairness, reflected by a trend reduction in inequality-aversion compared with placebo. Although MDMA is reported to be an 'empathogen' and has been shown to produce increased self-ratings of prosocial feelings (Dumont et al., 2009) and sociability (Bedi et al., 2009; Bedi et al., 2010), this is the first study that actually observed enhanced emotional empathy in men using an empathy test. In addition, the study also documented increased MDMA-induced prosociality in men in a behavioral task.

MDMA did not alter cognitive empathy in the MET and impaired emotion recognition of basic emotions in the FERT especially in women, consistent with impaired cognitive empathy with regard to decoding of basic emotions. Specifically, MDMA reduced the recognition of negative facial emotions, including fear, anger and disgust, consistent with the reduced recognition of fearful faces in a static FERT (Bedi et al., 2010) and the impaired mind-reading accuracy of negative emotions in the RMET (Hysek et al., 2012b). MDMA did not affect the recognition of happy faces as previously shown (Bedi et al., 2010), while improved recognition of happy expressions in the RMET was found in another study (Hysek et al., 2012b). MDMA reduced affect recognition accuracy particularly in women. The largest MDMA-induced deficit in women was found in fear recognition and involved both accuracy and intensity detection thresholds. A functional imaging study showed that MDMA enhanced the response to happy faces in the ventral striatum (Bedi et al., 2009), a structure activated by expected rewards (Knutson and Cooper, 2005), and attenuated the response to angry faces in the amygdala, which is a core region for fear processing (Zald, 2003). Because women generally exhibit greater left amygdala activation to negative emotional stimuli than men (Stevens and Hamann, 2012), MDMA may alter emotional processing in a valence- and sex-specific manner by modulating the brain circuits involved in the processing of reward and anxiety.

The findings from the MET and FERT indicate that MDMA overall enhances the emotional but not cognitive components of empathy. More specifically, MDMA appears to reduce the recognition of negative but not positive emotions in others across different tests and studies. Altogether, these effects of MDMA likely result in a shift in the processing of social–emotional information toward enhanced perception and possibly responses to positive emotional stimuli. Both the positive and prosocial mood effects and valence-specific social cognitive effects of MDMA likely enhance sociability when MDMA is used as a club drug. The effects of MDMA on social cognition may also facilitate the processing of emotionally distressing material when MDMA is used in combination with psychotherapy for patients with social dysfunction and social threat such as post-traumatic stress disorder and social anxiety disorder (Mithoefer et al., 2013).

Sex differences in various effects of MDMA have previously been described. MDMA produced more intense acute subjective effects (Liechti et al., 2001) and greater negative long-term effects (Reneman et al., 2001; Ogeil et al., 2013) in women compared with men. Women also more frequently developed hyponatremia in association with ecstasy use compared with men (Rosenson et al., 2007; van Dijken et al., 2013). These findings indicate that women may be generally more susceptible to the effects MDMA compared with men. Consistently, we observed MDMA-induced deficits in the recognition of sad faces only in women but not in men and significantly greater deficits in the recognition of fearful faces in women compared with men. A reduced ability to detect and process negative emotional information is likely therapeutically relevant when MDMA is used in the treatment of post-traumatic stress disorder. It will be of interest to see whether there are sex differences in the treatment response to MDMA in clinical studies, which have so far included 85% women (Mithoefer et al., 2010; Mithoefer et al., 2013; Oehen et al., 2013).

In this study, we documented increased levels of oxytocin, cortisol and prolactin along with alterations in emotional cognition. However, we found no correlations between MDMA-induced endocrine and emotional changes. The lack of associations does not exclude a role for oxytocin in the empathogenic and prosocial effects of MDMA as discussed below. There are several possible reasons for the lack of significant correlations. First, circulating levels of neurohormones may not reflect their brain levels (Neumann, 2007). Second, blood drawings to determine the endocrine markers had to be done before or after the computer tasks for practical reasons. Third, the use of only one relatively high dose of MDMA likely resulted in maximal threshold effects precluding the detection of correlations between the endocrine biomarkers and emotional measures across subjects. We have previously documented an identical lack of correlations between the subjective and autonomic effects of MDMA across a large number of subjects once peak drug effects are reached while there are strong associations over time within subjects (Hysek and Liechti, 2012).

Which neurotransmitters or hormones may contribute to the effects of MDMA on social cognition? The primary mechanism of action of MDMA is to release serotonin and norepinephrine in the brain, and both neurotransmitters have been shown to mediate most of the acute psychotropic effects of MDMA (Hysek et al., 2011, 2012d). Serotonin and norepinephrine release also likely mediates the effects of MDMA on emotional processing. In fact, we previously demonstrated that the inhibition of MDMA-induced serotonin and norepinephrine release with duloxetine not only prevented the subjective effects of MDMA (Hysek et al., 2012d) but also tended to reduce the effects of MDMA on emotion identification in the RMET (Hysek et al., 2012b). Similar to MDMA, the 5-HT1A/2A receptor agonist psilocybin impaired the recognition of negative facial expressions in healthy subjects, and this effect was prevented by a 5-HT2A antagonist (Kometer et al., 2012). In addition, serotonin transporter inhibitors, such as citalopram, also alter emotional processing, depending on emotional valence (Anderson et al., 2011), and generally increase the recognition of positive facial emotions (Harmer et al., 2003a) and diminish the perception of negative emotions (Pringle et al., 2013), including fear (Harmer et al., 2004) and sadness (Hinkelmann et al., 2010). Furthermore, polymorphisms in the serotonin transporter gene were also associated with altered emotion recognition, particularly of fearful faces (Hinkelmann et al., 2010). Serotonin is also a supposed regulator of social behavior. Enhancing serotonin via transporter inhibition increases aspects of prosocial behavior (Knutson et al., 1998; Crockett et al., 2010), whereas tryptophan depletion decreases cooperative behavior (Wood et al., 2006). Finally, the norepinephrine transporter inhibitor reboxetine increased the recognition of happy faces and impaired the recognition of fearful faces (Harmer et al., 2003b, 2004), similar to MDMA. Altogether, the effects of the serotonin and norepinephrine releaser MDMA on emotional processing and social behavior are consistent with the effects reported for other pharmacological manipulations of these neurotransmitters. However, the extent to which downstream stimulating effects on social neuropeptides and hormones are involved is unclear. Oxytocin is a key candidate for the mediation of the empathic and prosocial effects of MDMA (Thompson et al., 2007; Hysek et al., 2012b). MDMA activates oxytocin neurons, increases plasma oxytocin levels through 5-HT1A receptors and increases social interaction in rats (Thompson et al., 2007). Blocking oxytocin receptors in the brain reduced the prosocial effects of MDMA in rats (Thompson et al., 2007). In this study, MDMA increased the plasma levels of oxytocin in parallel with its empathogenic and prosocial effects. Increases in plasma oxytocin have previously been shown after MDMA administration (Dumont et al., 2009; Hysek et al., 2012b). The empathogenic effects of MDMA in the MET are also strikingly similar to those of oxytocin in the same test (Hurlemann et al., 2010). Analogous to MDMA, oxytocin enhanced emotional but not cognitive empathy in the MET in men (Hurlemann et al., 2010). In the RMET, oxytocin improved emotion recognition in healthy subjects (Domes et al., 2007) and patients with autism (Guastella et al., 2010). MDMA similarly improved emotion recognition in the RMET, although only for positive stimuli (Hysek et al., 2012b). A comparable selective increase in the sensitivity in detecting positive vs negative facial expressions was also reported for oxytocin (Marsh et al., 2010). Similar to the effects of MDMA in the FERT in this study, oxytocin slowed reaction times for identifying fearful faces (Di Simplicio et al., 2009). Both MDMA and oxytocin reduced the response of the amygdala to negative emotional stimuli (Kirsch et al., 2005; Bedi et al., 2009). Comparable to the prosocial effects of MDMA, oxytocin has been shown to increase generosity (Zak et al., 2007) and trust (Kosfeld et al., 2005). The MDMA-induced release of oxytocin and overall very similar emotional-cognitive effects of oxytocin and MDMA might implicate oxytocin as a crucial mediator of the effects of MDMA on empathy and social behavior. Directly testing the role of oxytocin in the effects of MDMA in humans will be difficult because clinically used oxytocin receptor antagonists or PET ligands do not cross well the blood–brain barrier (Smith et al., 2012). MDMA response modulation by genetic polymorphisms in the oxytocin receptor gene (e.g. rs53576 and rs1042778) (Kumsta and Heinrichs, 2013) could be tested. In addition, effects of MDMA or of pharmacologically similar but less toxic drugs could be evaluated in patients with social dysfunction where oxytocin is implicated such as autism (Guastella et al., 2010). As expected (Harris et al., 2002), MDMA also increased the plasma levels of cortisol and prolactin. Cortisol and prolactin are primarily markers of hypothalamic–pituitary–adrenal, serotonergic and noradrenergic activity but there are limited data on the role of cortisol in social cognition. In men, high stress-induced cortisol levels were associated with better social cognition (Smeets et al., 2009).

This study has limitations. First, we used only one dose of MDMA. We did not perform a dose–response study because we did not want to expose the mostly drug-naïve subjects to more than two doses of MDMA. Second, we used a relatively high dose of MDMA with obvious subjective effects. Although we used a double-blind design and identical placebo most participants realized which treatment they had been administered over the course of the experimental session. Thus, unblinding the subjective effects of MDMA may have biased task performance. We felt that it is important to use relevant doses of MDMA, which correspond to those typically used in recreational settings (Brunt et al., 2012) or in clinical trials (125 mg plus 62.5 mg after 2 h) (Mithoefer et al., 2010; Mithoefer et al., 2013; Oehen et al., 2013). Lower doses of MDMA and active placebo could be used in future studies. Third, the evaluation of many aspects of social cognition in this study required a relatively large number of statistical comparisons.

In summary, the novel findings are that MDMA increases emotional empathy and prosocial behavior in healthy subjects. The social cognitive effects of MDMA may explain its popularity as a recreational drug and potential beneficial effects of MDMA in the treatment of 'social disorders' and post-traumatic stress disorder.

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