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\begin{document}

\title{MDMA enhances early visual processing for salient socio-emotional
stimuli.}



\author[1]{Connor Haggarty}%
\author[2]{Anya Bershad}%
\author[3]{Mahesh Kumar}%
\author[3]{Royce Lee}%
\author[3]{Harriet de Wit}%
\affil[1]{Wayne State University}%
\affil[2]{UCLA Semel Institute for Neuroscience and Human Behavior}%
\affil[3]{University of Chicago Biological Sciences Division}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{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.%
\end{abstract}%



\sloppy


\textbf{MDMA enhances early visual processing for salient
socio-emotional stimuli.}

Connor J. Haggarty\textsuperscript{1}, Anya K.
Bershad\textsuperscript{2}, Mahesh K. Kumar\textsuperscript{1}, Royce
Lee\textsuperscript{1}, Harriet de Wit\textsuperscript{1*}.

Department of Psychiatry and Behavioral Neuroscience, University of
Chicago, IL, USA.

Semel Institute for Neuroscience and Human Behavior, University of
California Los Angeles, CA, USA

\textbf{Corresponding Author:}

Harriet de Wit Psychiatry and Behavioral Neuroscience, University of
Chicago, Chicago, IL, US, 60637 *hdew@uchicago.edu

\textbf{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.

\textbf{Key words:} EEG, MDMA, Methamphetamine, Faces, Emotion

\textbf{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 (Carreti\selectlanguage{ngerman}é 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.

\textbf{Materials and Methods.}

\emph{Design.} The study used a double-blind, within-participant design
in which healthy adults received MDMA (100mg), MA (20mg) and placebo
(PLC) on three separate sessions. At the expected time of peak drug
effect participants engaged in an oddball task during which we recorded
EEG responses to positive, negative, and neutral faces. ERP components
related to different aspects of emotional and cognitive processing were
recorded. Participants also completed self-report measures of the drugs'
effects.

\emph{Participants.} Healthy men and women (N=25) aged 18-35 were
recruited from the university and surrounding neighborhoods. Eligibility
was determined first by online screening and then by clinical interview
and physical examination. Inclusion criteria consisted of a minimum high
school education, fluency in English, BMI 18-26, and good health.
Exclusion criteria included use of prescription medications, history of
cardiac disease or high blood pressure and previous negative experience
with MDMA or hallucinogenic substances. Participants had to report
between 4 and 40 previous experiences of MDMA to qualify for the study.
Women who were not on oral contraceptives were tested only during the
follicular phase (1-12 days from menstruation; White, Justice et al.
2002).

\emph{Procedure.} Participants first attended an orientation to
understand the procedures, provide informed consent and practice the
tasks from the experimental sessions. They were instructed to abstain
from drugs and alcohol for 24 hours before their sessions. They were
told they would receive a \emph{sedative (e.g., Valium)}
,\emph{stimulant (e.g., MDMA or amphetamine),} or \emph{placebo} drug in
each session. The study was approved by the local institutional review
board.

The three, four-hour drug sessions were conducted from 9am-1pm,
separated by at least 4 days (M=7.5 days). Upon arrival at the
laboratory, participants completed a breathalyzer and urine sample to
test for recent drug use (CLIA waived Instant Drug Test Cup, San Diego,
CA; amphetamine, cocaine, oxycodone, THC, PCP, MDMA, opiates,
benzodiazepines, barbiturates, methadone, methamphetamine,
buprenorphine), alcohol use (Alcosensor III, Intoximeters, St. Louis,
MO) and pregnancy (in females; Aimstrip, Craig Medical, Vista, CA). They
completed pre-capsule questionnaires and cardiovascular measures,
measures that were repeated 60, 90, 180 and 240 minutes after the
capsule. They ingested capsules containing dextrose (placebo), MA (20mg)
or MDMA (100mg) under double blind conditions. Thirty minutes after
taking the capsule participants' EEG electrodes were placed, and
recording began about 60 minutes after the capsule. Resting state EEG
was determined first, and this was followed by three tasks completed in
randomized order. Here we report data on an emotional oddball task
assessing responses to happy, angry, and neutral faces (Raz et al.,
2014). The EEG measures were obtained from 60 to 150 min post-capsule.
After the EEG electrodes were removed, participants rated the arousal
and valence of the faces they viewed during the EEG task. Participants
left the laboratory after the final measure, 240 min post capsule.

\textbf{Drugs:} MDMA in powdered form (100 mg; Organix Inc, MA) was
placed in opaque size 00 capsules with lactose filler. MA tablets (5 mg,
total dose 20 mg; Desoxyn, Lundbeck) were placed in an opaque size 00
capsule with dextrose filler, and placebo capsules contained only
dextrose.

\emph{Self-Report Measures.}

\begin{enumerate}
\tightlist
\item
  The \emph{Drug Effects Questionnaire} (DEQ; Morean et al., 2013) The
  DEQ consists of 100 point visual analog scales (VAS) describing
  responses to the drug. Here we focused only on the questions ``Do you
  like the effects that you are feeling now?'' (``Not at all'' (0) to
  ``Very much'' (100)) and ``Would you like more of what you consumed,
  right now?'' (``Not at all'' (0) to ``Very much'' (100)).
\item
  \emph{Visual Analogue Scales (VAS)} . The VAS consisted of 14 words
  describing drug-like experiences. Here we present data from the words
  ``Sociable'' and ``Friendly''. Participants rated on a 100-point scale
  how strongly they felt those feelings (`not at all' to `extremely') at
  each of the five time points during each session.
\item
  The \emph{Session End Questionnaire} (SEQ). The SEQ consists of
  questions relating to the drug received during the session.
  Participants indicated how pleasant they found the experience (from
  `dislike' (0) to `like very much' (100)) and what they thought they
  had received (i.e., Valium, Ketamine, Amphetamine, MDMA, LSD,
  Placebo).
\end{enumerate}

\emph{EEG Measures.}

Data collection and Processing. A 64 channel electro-geodesic net was
used (Magstim, EGI). Electrodes were soaked in a saline solution then
placed on the head using measurements from nasion to inion and mastoid
to mastoid. EEG data was acquired continuously, amplified, and digitized
using Netstation software, sampled online at 1024Hz. Offline EEG
recordings were analyzed using EEGLab (Delorme \& Makeig, 2004) it was
first down sampled to 512Hz then high pass filtered (1 Hz), and low pass
filtered (60 Hz, -12 dB/octave) to remove extraneous high and low
frequency noise. Data were visually inspected for movement and
electronic artifact. PICARD Independent Components Analysis (Ablin,
Cardoso \& Gramfort, 2017) were performed to correct for EEG artifacts
including blinks, horizontal and vertical eye movements, muscle movement
and EKG signal. Data were segmented from -200 to 1000ms and baseline
corrected following stimulus presentation for each of the stimulus
types.

\textbf{Emotional Oddball Task (Raz et al., 2014).} To assess the neural
responses to emotional stimuli, participants completed an emotional
oddball task. The task consisted of 300 stimulus presentations, of which
80\% were cartoon faces, and 20\% were human faces. The stimuli were
presented in three blocks of 100 stimuli consisting of the frequent
cartoon image interspersed with infrequent angry, happy, or neutral
faces. Subjects were instructed to respond on the left key on a button
box when they saw a human face and, on the right when they saw a cartoon
face. ERPs were recorded during each stimulus presentation.

\emph{Behavioral Measure.}

\textbf{Face Ratings Task.} Following the EEG session participants
completed a ratings task in which they rated the 6 faces presented in
the oddball task for valence and arousal. Valence and arousal were rated
on a Likert scale from -4 (Very Negative/ Not at all) to +4 (Very
Positive/Extremely). Participants were told to indicate how positive or
negative they perceived each face (valence) and how strongly they felt
that emotion (arousal) (Supplementary Figure 1).

\emph{Analysis.}

\begin{enumerate}
\tightlist
\item
  Subjective and behavioral measures were assessed with analysis of
  variance using peak change score from baseline, using individual
  paired samples T-tests to measure the differences between Placebo vs
  MA and Placebo vs MDMA. Peak drug effects were calculated by
  subtracting the baseline values from the highest or lowest value
  during the session.
\item
  Faces Ratings Task (supplementary results). Participants rated the
  valence and arousal of each of the 6 faces seen in the emotional
  oddball task (male and female; angry, happy, neutral). These ratings
  were analyzed using two 3x2 (Emotion x MDMA (vs PLC); Emotion x MA (vs
  PLC)) ANOVAs.
\item
  Emotional Faces Oddball Task. The N170 was measured at electrode PO8,
  extracting the mean peak from 150-200ms post stimulus onset. The P300
  was measured at electrode parietal (Pz) extracting the mean peak
  between 300-400ms. The MMN was measured using electrodes Fz between
  240-350ms. For each of these peaks of interest, two 3 (Emotion) x 2
  (Drug condition; Drug vs PLC) repeated measures ANOVAS were conducted.
  We also examined ERP responses to the frequent cartoon faces for MMN
  to compare frequent vs infrequent stimuli. Initial analyses
  (supplementary materials) revealed that responses to the (infrequent)
  human faces differed from markedly from responses to the (frequent)
  cartoon face on all three ERP measures. The final analyses were
  conducted only with the human faces, comparing MDMA and MA vs PLC
  separately.
\end{enumerate}

\textbf{Results} .

Demographics. Participants were 17 men and 8 women, mean age of 27.4
years, most of whom had completed partial college (Table 1).
Participants had previously taken MDMA a mean of 7.1 times. None of the
subjects were cigarette smokers. Sixty-four percent of participants
correctly identified Placebo, 20\% MA and 52\% MDMA, showing the
effectiveness of the blinding (Supplementary Table 1).

\textbf{Table 1} . Demographic information and nonmedical drug use
(N=25).\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Sex (number M/F) & & (17, 8)\tabularnewline
Age (mean and sem) & & 27.4 (4.2)\tabularnewline
BMI (mean and sem) & & 23.1 (2.8)\tabularnewline
Years in Education (mean and sem) & & 16.1 (1.7)\tabularnewline
Ethnicity (percent of sample) & Caucasian/White & 58\%\tabularnewline
& African American & 13\%\tabularnewline
& Asian & 17\%\tabularnewline
& Other/More than one & 13\%\tabularnewline
Recent Drug Use (last 30 days) & &\tabularnewline
& Alcohol (drinks/week) & 6.3 (5.0) {[}N=23{]}\tabularnewline
& Alcohol (drinks/occasion) & 2.7 (1.5) {[}N=23{]}\tabularnewline
& Alcohol (occasions/week) & 2.0 (1.6) {[}N=23{]}\tabularnewline
& Caffeine (cups/day) & 1.4 (1.0) {[}N=20{]}\tabularnewline
& Cannabis (uses/30 days) & 6.5 (7.9) {[}N=19{]}\tabularnewline
Lifetime MDMA (uses) & & 7.1(10.1) {[}N=25{]}\tabularnewline
\textbf{Note.} Drug use data are represented as Mean (SEM) of uses only
for the participants who reported ever using the drug {[}N{]}. &
\textbf{Note.} Drug use data are represented as Mean (SEM) of uses only
for the participants who reported ever using the drug {[}N{]}. &
\textbf{Note.} Drug use data are represented as Mean (SEM) of uses only
for the participants who reported ever using the drug
{[}N{]}.\tabularnewline
\bottomrule
\end{longtable}

\emph{Subjective Measures.} MDMA increased ratings of Drug liking
relative to PLC (t(24)=-3.93, \emph{p=} .001) but MA did not differ from
PLC (t(24)=-2.00, \emph{p=} .06). Both MDMA and MA increased wanting
more drug ratings compared to PLC (MDMA, t(24)=-3.32,\emph{p=.} 003; MA,
t(24)=-2.38, \emph{p=.} 03). For VAS ratings, MDMA significantly
increased feelings of friendliness compared to PLC (t(23)=-2.06,
\emph{p=} .05), as did MA (t(23)=-2.15, \emph{p=} .04).In contrast, MA
but not MDMA increased feelings of sociability (t(24)=-2.14, \emph{p=04}
) (Figure 1).

\textbf{{[}Figure 1 here{]}}

\textbf{Figure 1.} Mean and sem for ratings of Liking, Wanting More,
feelings of Friendly and Sociable for PLC (green), MA (blue) and MDMA
(red) sessions. MDMA significantly increased ratings for liking drug
effects, wanting more of the drug and how Friendly participants felt,
compared to placebo, whereas MA significantly increased ratings of
wanting more drug, Friendly and Sociable.

\emph{Session End Questionnaire}\textbf{.} On the end of session
questionnaire, 64\% of participants correctly identified PLC, 20\% of
participants correctly identified MA as a stimulant, and 52\% correctly
identified MDMA (full breakdown in supplementary results). Subjects
reported liking MDMA (mean=78.0) and MA (mean=71.2) more than PLC
(mean=48.2).

\emph{Drug Effects on ERP peaks.}

N170 -- Face processing. (Figure 2). MDMA significantly increased N170
peak amplitude compared to PLC specifically for Happy (MDMA/PLC;
M=-2.27\selectlanguage{greek}µ\selectlanguage{english}V/M=-1.04 \selectlanguage{greek}µ\selectlanguage{english}V) and Angry (MDMA/PLC; M=-2.09\selectlanguage{greek}µ\selectlanguage{english}V /M=-1.31\selectlanguage{greek}µ\selectlanguage{english}V) faces
(significant Drug x Emotion interaction, F(2,86)= 4.49, \emph{p=.01} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.1). Regardless of whether
participants received MDMA or PLC, the N170 amplitude was also greater
with Happy and Angry faces compared to Neutral faces (main effect of
Emotion F(2,88)= 7.86, \emph{p=.001} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.15). MA did not affect the N170
peak amplitude, compared to PLC (no significant interaction between Drug
and Emotion, F(2,86)= 0.31, \emph{p\textgreater{}.05} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.007). In this MA vs PLC
analysis, Emotion did not affect peak N170 amplitude here (no main
effect of Emotion, F(2,86)= 1.21, \emph{p\textgreater{}.05} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.03).

\textbf{{[}Figure 2 here{]}}

\textbf{Figure 2} . \emph{N170} ERPs at electrode PO8 (shaded area) for
Happy, Angry and Neutral faces. ERPs are shown for PLC (blue), MA (red)
and MDMA (green) faces. MDMA significantly increased N170 peak amplitude
in response to Happy and Angry faces, but not Neutral faces when
compared with PLC.

P300 -- Emotion processing. (Figure 3). MDMA did not affect the P300
peak amplitude compared to PLC (no significant interaction between Drug
and Emotion (F(2,86)= 1.36,\emph{p\textgreater{}.05} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.05\emph{)} or main effect of
Drug, (F(2,86)= 3.37, \emph{p=.07} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.07)). Similarly MA did not
affect P300 (no significant interaction with Emotion (F(2,88)=
2.20,\emph{p\textgreater{}.05} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.05) or main effect of Drug
(F(2,86)= 0.14, \emph{p\textgreater{}.05} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.003)). Emotion was not
significantly related to P300 peak for either MDMA or MA vs PLC (MDMA:
F(2,86)= 2.02, \emph{p\textgreater{}.05} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.05; MA: F(2,86)=
0.72,\emph{p\textgreater{}.05} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.02) (Figure 3).

\textbf{{[}Figure 3 here{]}}

\textbf{Figure 3.} ERPs at electrode Pz. Shaded area represents P300
peak amplitudes for Happy (top), Angry (bottom left) and Neutral (bottom
right) Faces with ERPs shown for PLC (blue), MA (red) and MDMA (green)
sessions. Neither MDMA nor MA affected the peak amplitude of P300 ERPs.
There was also no effect of Emotion on the P300 response.

MMN -- Novelty processing. (Figure 4). MDMA did not affect MMN amplitude
compared to PLC (no interaction between Drug and Emotion (F(3,129)=
0.91, \emph{p\textgreater{}.05} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.02) and no main effect of Drug
(F(1,43)= 0.48, \emph{p\textgreater{}.05} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.01)). MA also did not affect the
MMN peak amplitude (no significant interaction (F(3,129)=
0.51,\emph{p\textgreater{}.05} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.01) and no main effect of Drug
(F(1,43)= 0.90, \emph{p\textgreater{}.05} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.02)). The type of face shown,
however, did affect peak amplitude in PLC and MDMA sessions (F(3,129)=
39.00, \emph{p\textless{}.001} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.48) with Human faces resulting
in a significantly greater MMN than Cartoon faces (all
ps\textless{}.001). This was expected because MMN signals
novel/infrequent stimuli. Similarly, in the analysis of MA vs PLC face
type significantly affected MMN amplitude whereas drug type did not
(F(3,129)= 37.14, \emph{p\textless{}.001} ,
\selectlanguage{greek}η\selectlanguage{english}\textsubscript{p}\textsuperscript{2}=0.46) again with Human faces
resulting in a significantly greater MMN than the Cartoon face (all
ps\textless{}.001) (Figure 4).

\textbf{{[}Figure 4 here{]}}

\textbf{Figure 4.} ERPs at electrode Fz. Shaded area represents MMN peak
amplitudes for Happy (top), Angry (bottom left), Neutral (bottom right)
and Cartoon (dashed) Faces with ERPs shown for PLC (blue), MA (red),
MDMA (green) sessions. MDMA and MA did not affect the peak amplitude of
MMN however MMN was present for human faces compared to cartoon faces.
Furthermore, MMN was not affected by the emotion of the face
shown\textbf{.}

\textbf{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.

\textbf{CRediT}

\textbf{Connor Haggarty} : Conceptualization, Data curation, Formal
analysis, Investigation, Methodology, Project administration,
Visualization, Writing -- original draft, Writing -- review \&
editing.\textbf{Anya Bershad} : Conceptualization, Formal analysis,
Project administration, Writing -- review \& editing.
\textbf{Mahesh~Kumar:}Data curation, Formal analysis, Investigation,
Visualization\textbf{Royce Lee} : Conceptualization, Data curation,
Formal analysis, Writing -- review \& editing \textbf{Harriet de Wit:}
Conceptualization, Data curation, Formal analysis, Funding acquisition,
Investigation, Methodology, Project administration, Supervision, Writing
-- original draft, Writing -- review \& editing.

\textbf{Funding} This research was supported by USPHS DA02812.

\textbf{Data Availability} -- Data is available raw or processed on
request to the corresponding author

\textbf{Competing interests -} HdW serves on the Board of Directors of
PharmAla Biotech and has served as Scientific Advisor to Awakn Life
Sciences, Gilgamesh Pharmaceuticals and Mind Foundation. These roles are
unrelated to the research reported here. CJH, AKB, MK, and RL have no
conflicts of interest to disclose.



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