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.