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.