Discussion .
The current study investigated the effects of two drugs, MDMA and MA, compared to placebo, on evoked potential responses to emotional stimuli in healthy adults. The two drugs produced their expected subjective effects. MDMA increased the N170 peak amplitude for happy and angry faces compared to neutral faces, but MA did not have this effect. The N170 is thought to reflect processing of facial features and is sensitive especially to emotional faces. Neither drug significantly altered P300 or MMN evoked potentials which are thought to reflect attention allocation and cognitive processing (P300) and responses to novelty (MMN).
Both MDMA and MA had expected effects on subjective and behavioral measures. Both MDMA and MA increased ratings of liking the drug effect and wanting more of the drug. Both drugs also increased feelings of friendliness whereas only MA increased feelings of sociability. The lack of effect of MDMA on sociability was surprising considering some previous reports (Kirkpatrick et al., 2014), and because MDMA is often described as a pro-social drug. It is known that social context can influence responses to MDMA (Kirkpatrick and de Wit., 2015), and so it is possible that the solitary laboratory environment in the present study prevented the drug from producing feelings of sociability. Although as expected, participants rated happy faces more positively than neutral faces, and angry faces more negatively than neutral faces, neither MDMA nor MA altered these ratings.
The main finding in this study was that MDMA, but not MA, enhanced the N170 amplitude in response to salient emotional faces. The drug increased N170 signals with happy and angry, but not neutral, faces. To our knowledge, the effects of MDMA and MA on N170 ERPs have not previously been examined. The N170 is thought to represent early structural encoding of face stimuli, especially faces expressing emotions (Bentin et al., 1996). Emotional states can enhance the peak of this ERP (Blau et al., 2007; Qui et al., 2017). Interestingly, the prosocial hormone oxytocin reportedly increases N170 responses to faces, especially sad faces (Peltola et al., 2018). The finding that the pro-social drug MDMA, like oxytocin, increased N170 responses to emotional faces is consistent with the idea that the N170 signals early social approach/avoidance behaviors (Schlindler & Bublatzky., 2020). The present finding suggests that MDMA may affect early visual processing of socially salient stimuli, which then affects later processing functions (Hysek et al., 2014; Kirkpatrick et al., 2014; Wardle & de Wit., 2014; Bershad et al., 2016). MDMA has also been shown to increase the recall of positive and emotional memories but do not affect neutral ones, which is consistent with the idea that MDMA indeed enhances emotional processing (Doss et al., 2017). MA, which has less pronounced effects on social processes (Bershad et al, 2016), did not affect the N170. It is important to consider also that there is evidence to suggest that long term MDMA use may impact social functioning differently. For example, Wunderli and colleagues (2018) reported that long term MDMA users showed enhanced cognitive empathy but not emotional empathy. Comparatively Carlyle and colleagues (2019) showed that both cognitive and emotional empathy were enhanced in the MDMA users. These are important considerations for social functioning in long-term use of MDMA as a pharmaceutical.
Contrary to our expectations, neither MA nor MDMA affected the P300 peak amplitude. The P300 is thought to reflect attention allocation and cognitive processing, and thus might be expected to be greater with drugs that increase attention, or with more salient stimuli (emotional faces). In the present study, the P300 was not affected by either of the two drugs or by emotion (angry or happy compared to placebo), although we did find that the P300 was smaller with cartoon faces compared to human faces. This suggests that the P300 is sensitive to faces but not emotions, although the cartoon faces were also presented much more frequently than the human faces. The P300 is thought to reflect cognitive processing related to attention and orientation (Morgan et al., 2008; Mueller et al., 2017). The lack of effect of either MDMA or MA on P300 is somewhat surprising, considering that both drugs are considered stimulants, which are thought improve attention. Moreover, MDMA has been shown to increase visual attention to happy faces compared to other emotions (Bershad et al., 2019), but this effect was not detected here with related EEG measures. Thus, the effects of MDMA and MA attention likely vary, depending on the measures that are used to assess attention, as well as the doses and participants studied (Cami et al., 2000; Silber et al., 2006).
The MMN ERP was not affected by either MDMA or MA. Because the MMN is thought to signal a response to novel stimuli, this suggest that neither drug increased neural response to novelty. Our finding that the MMN ERP was greater with the infrequent human faces than frequent cartoon faces indicates that the measure was sensitive to this indicator of novelty. However, the finding that neither drug affected MMN suggests that they did not affect processing of novelty of the emotional faces. Although there is indirect evidence that stimulants increase salience of stimuli (Taylor and Robbins., 2007; Chaudhri et al., 2007), few other studies have examined effects of stimulants specifically on MMN amplitude. In one of few reports of drug effects on MMN, single doses of the selective serotonin uptake inhibitor escitalopram significantly increased MMN, without affecting P300 amplitude (Wienberg et al., 2010). Further research is needed to determine whether, or how, stimulant drugs affect this neural indicator of novelty.
The study had several limitations. The sample was homogeneous, limited to healthy men and women aged 18-35, who had previously used MDMA. Thus, the results may not be generalizable to a more heterogeneous population including those with greater or lesser drug use histories. While the sample size was within the typical size for studies involving EEG recordings, it is likely that more subtle effects would be detected with a larger sample. The study used only single doses of MDMA and MA, making it difficult to compare across drugs. That is, higher or lower doses of either drug likely produce different effects, and future studies with dose-responses are critical. MA is seven times more potent than MDMA at inhibiting noradrenaline transporters (Simmler et al., 2012), therefore it is important to consider that an extremely high dose of MDMA would be required to appropriately compare these drugs together, for this reason the drugs were compared separately compared to PLC. In future studies it would be beneficial to accurately match doses for their potency. Finally, the study was limited by the task that was used, and it is possible that the emotional faces oddball task is not optimal to detect the effects of these drugs. In future studies more complex studies of social behavior and motivation may parse the effects that MDMA is having on these processes.
The main finding in this study was that MDMA, but not MA, increased the N170 peak amplitude for angry and human faces, compared to neutral faces. This finding is consistent with evidence that the N170 is selective for faces and sensitive to emotion. The effect of MDMA on N170 is consistent with both the known function of this ERP, with evidence that MDMA affects responses to social stimuli. An interesting and important future direction is to clarify whether MDMA equally affects both positive and negative emotional stimuli, as the present data suggest. This would have implications for its use in therapeutic settings. The finding that MA did not have similar effects suggests MDMA differs from other stimulants in the processing of social stimuli, although this conclusion must await testing with a full range of doses.