Abstract .
3,4-methylenedioxymethamphetamine (MDMA) has long been used
non-medically, and it is currently under investigation for its potential
therapeutic benefits. Both uses may be related to its ability to enhance
empathy, sociability, emotional processing and its anxiolytic effects.
However, the neural mechanisms underlying these effects, and their
specificity to MDMA compared to other stimulants, are not yet fully
understood. Here, using electroencephalography (EEG), we investigated
the effects of MDMA and a prototypic stimulant, methamphetamine (MA), on
early visual processing of socio-emotional stimuli in an oddball
emotional faces paradigm. Specifically, we examined whether MDMA or MA
enhance the processing of facial expressions, compared to placebo,
during the early stages of visual perception. MDMA enhanced an
event-related component that is sensitive to detecting faces (N170),
specifically for happy and angry expressions compared to neutral faces.
MA did not affect this measure, and neither drug altered other
components of the response to emotional faces. These findings provide
novel insights into the neural mechanisms underlying the effects of MDMA
on socio-emotional processing and may have implications for the
therapeutic use of MDMA in the treatment of social anxiety and other
psychiatric disorders.
Key words: EEG, MDMA, Methamphetamine, Faces, Emotion
Introduction .
3,4-methylenedioxymethamphetamine (MDMA) is a stimulant-like drug with
both nonmedical and potential medical uses. Like other stimulants, it
increases dopaminergic and noradrenergic signaling, but its effects on
serotonin receptors are greater than those of other stimulants (Gough,
Slikker & Holson, 1991; Kalant., 2001; Luethi & Liechti., 2020). MDMA
is used recreationally, apparently for its euphoric and empathogenic
effects, and it is in Phase 3 trials as an adjunctive treatment, with
psychotherapy, for post-traumatic stress disorder (PTSD, Mitchell et
al., 2021). Despite the widespread use of the drug and its great promise
as a therapeutic agent, the specific behavioral and neural effects of
MDMA are not fully understood.
MDMA increases subjective and objective indices of sociability, social
perception, and empathy (Kamilar-Britt & Bedi., 2015; Bershad et al
2016). It increases self-reported feelings of empathy, openness, and
social connectedness, and decreases social anxiety and fear (Hysek et
al., 2014; Borissova et al., 2020), effects that may enhance social
interactions. On behavioral tasks, MDMA reduces sensitivity to negative
emotions such as fear or anger (Bedi, Hyman & de Wit, 2010; Hysek et
al., 2014), and reduces social anxiety in some populations (Danforth et
al., 2018). It also increases generosity and increases the pleasantness
of social touch (Kirkpatrick et al., 2015; Bershad et al., 2019). These
laboratory findings complement users’ reports that the drug produces
prosocial and entactogenic effects (Peroutka et al, 1988). MDMA produces
increased effects on measures of social and emotional function (Bershad
et al., 2016; Holze et al., 2019; Nardou et al., 2019; Heifets et al.,
2019). These unique effects may be related to actions of MDMA on
serotonin and oxytocin, which are implicated in social behavior, stress,
and social bonding in animal models (Thompson et al., 2009) and humans
(Bedi et al., 2009; Bershad et al., 2016; Kuypers et al., 2018).
However, these neurochemical and behavioral actions have not yet been
related to the neural processes by which MDMA enhances responses to
socioemotional stimuli in healthy human volunteers.
Event-related potentials (ERPs) provide a sensitive measure of neural
reactivity to emotional stimuli. Images of emotional faces in an oddball
task elicit three distinctive ERP components: N170, P300 and mismatch
negativity (MMN). The N170 component is a negative waveform occurring
approximately 170 milliseconds after stimulus onset, that is thought to
reflect the processing of facial features and the structural encoding of
faces (Bentin et al., 1996). It has been shown that emotion can enhance
the peak of this ERP (Blau et al., 2007; Qui et al., 2017). The P300
component is a larger positive waveform that occurs approximately
300-500 milliseconds after stimulus onset. The P300 is thought to
reflect attention allocation and cognitive processing (Carretié et al.,
1997). Finally, the MMN component is a negative waveform that occurs
approximately 200-300 milliseconds after stimulus onset and appears to
respond to novel stimuli (Stefanics et al 2014). By examining these
components in response to emotional stimuli after administration of MDMA
or a comparison drug, we may be able to understand which neural
processes mediate the drug’s effects on responses to emotionally salient
stimuli.
Here we conducted a double-blind study examining effects of MDMA and MA,
compared to placebo, on EEG responses to emotional faces. We contrasted
MDMA to a prototypic amphetamine, MA, which is thought to lack the
strong prosocial effects of MDMA (Bershad et al, 2016). Healthy young
adults received MDMA (100 mg), MA (20 mg) or placebo during three
sessions. We measured electrophysiological responses to emotional and
neutral faces using an emotional oddball task. We hypothesized that
MDMA, but not MA, would enhance the N170 and P300 ERP components
associated with socioemotional processing specifically for more salient
stimuli.