<p class="first" id="d9261992e192">Social decision-making is fundamental for successful
functioning and can be affected
in psychiatric illness and by serotoninergic modulation. The Prisoner's Dilemma is
the archetypal paradigm to model cooperation and trust. However, the effect of serotonergic
enhancement is poorly characterized, and its influence on the effect of variations
in opponent behavior unknown. To address this, we conducted a study investigating
how the serotonergic enhancer 3,4-methylenedioxy-methamphetamine (MDMA) modulates
behavior and its neural correlates during an iterated Prisoner's Dilemma with both
trustworthy and untrustworthy opponents. We administered 100 mg MDMA or placebo to
20 male participants in a double-blind, placebo-controlled, crossover study. While
being scanned, participants played repeated rounds with opponents who differed in
levels of cooperation. On each round, participants chose to compete or cooperate and
were asked to rate their trust in the other player. Cooperation with trustworthy,
but not untrustworthy, opponents was enhanced following MDMA but not placebo (respectively:
odds ratio = 2.01; 95% CI, 1.42–2.84,
<i>p</i> < 0.001; odds ratio = 1.37; 95% CI, 0.78–2.30, not significant). Specifically,
MDMA
enhanced recovery from, but not the impact of, breaches in cooperation. During trial
outcome, MDMA increased activation of four clusters incorporating precentral and supramarginal
gyri, superior temporal cortex, central operculum/posterior insula, and supplementary
motor area. There was a treatment × opponent interaction in right anterior insula
and dorsal caudate. Trust ratings did not change across treatment sessions. MDMA increased
cooperative behavior when playing trustworthy opponents. Underlying this was a change
in brain activity of regions linked to social cognition. Our findings highlight the
context-specific nature of MDMA's effect on social decision-making.
</p><p id="d9261992e197">
<b>SIGNIFICANCE STATEMENT</b> We provide a detailed analysis of the effect of 3,4-methylenedioxy-methamphetamine
(MDMA) on cooperative behavior during interpersonal interactions, as well as the neural
correlates underlying these effects. We find that, following administration of MDMA,
participants behave more cooperatively, but only when interacting with trustworthy
partners. While breaches of trustworthy behavior have a similar impact following administration
of MDMA compared with placebo, MDMA facilitates a greater recovery from these breaches
of trust. Underlying this altered behavior are changes in brain activity during the
viewing of opponents' behavior in regions whose involvement in social processing is
well established. This work provides new insights into the impact of MDMA on social
interactions, emphasizing the important role of the behavior of others toward us.
</p>