MDMA attenuated amygdala reactivity to angry, but not fearful, faces, while enhancing ventral striatum response to happy faces. As expected, MDMA also increased subjective sociability at 1.5mg/kg. These findings suggest that MDMA alters processing of emotionally salient social information in at least two ways, by reducing responses to threat and by enhancing responses to reward.
Here, we investigated neural mechanisms that may mediate this increase in sociability, by studying neural responses to emotional stimuli. We found that MDMA both dampened neuronal responses to threat-related social stimuli and increased responses to positive social images, suggesting that these processes may contribute to the drug’s prosocial effects. The findings regarding threat-related stimuli are consistent with other imaging studies investigating responses to socioemotional material. Two other drugs that purportedly decrease social anxiety, THC (Phan et al. 2008
) and alcohol (Gilman et al. 2008
), also attenuate limbic responses to social threat (Gilman et al. 2008
; Phan et al. 2008
). Individuals with social anxiety, who typically avoid social interactions, have heightened amygdala response to threat signals (Phan et al. 2006
); whereas those genetically predisposed towards exaggerated sociability have dampened amygdala reactivity to social threat (Meyer-Lindenberg et al. 2005
). OT administration attenuates limbic threat response (Kirsch et al. 2005
) and increases behavioral indicators of trust (Kosfeld et al. 2005
). Together, these previous findings suggest that dampened neural response to social threat leads to greater sociability. Our findings regarding increased responses to positive social stimuli are relatively novel, because there is little existing evidence regarding effects of drugs on social reward. However, the finding is consistent with a large body of evidence that activation of dopaminergic reward circuitry is critically important in human socioaffiliative behavior (Skuse and Gallagher, 2008
), supporting the hypothesis that enhanced social reward processing would also lead to heightened sociability.
The effects of MDMA were dose-dependent on some, but not all, measures. As has been reported previously (see Dumont et al. 2006
), the drug increased subjective sociability only at a higher dose. Similarly, MDMA attenuated amygdala response to angry faces only at the higher dose. Of note, however, was the apparent dissociation between self-report and VS recruitment in response to happy facial expressions. At the lower dose, MDMA enhanced neural response to happy faces without changing subjective sociability ratings. It is possible that brain responses to social stimuli are more sensitive indicators of prosocial effects, and that higher doses may be needed for individuals to report feeling more sociable. Moreover, it is not known whether the subjective experience of feeling social is essential for individuals to actually behave more sociably. Further research is required to clarify relationships between behavioral, subjective and neural dimensions of MDMA’s effects, and to better characterize active doses of MDMA in terms of sociability.
Neurobiological substrates of MDMA’s unusual effects are poorly understood (Thompson et al. 2007
). However, there is some evidence that they may be mediated through effects on both oxytocin and dopaminergic (DA) neurocircuitry. OT plays a key role in modulating attachment and affiliation, and OT antagonism attenuates the prosocial effects of MDMA in rodents (Thompson et al. 2007
). Ecstasy self-administration in humans is also associated with increased plasma OT levels (Wolff et al. 2006
). It has been suggested that the effects of OT on social behavior may involve interactions between OT systems and DA reward circuitry (Skuse and Gallagher, 2008
). This possibility has not been directly assessed in relation to MDMA. However, a recent study found that in rodents, MDMA administration in a social context produced greater neural activation than MDMA in isolation. Regions preferentially activated included some high in OT receptors and implicated in social behavior, as well as regions involved in the mesolimbic DA system, known to subserve reward (Thompson et al. 2009
). Thus, it may be hypothesized that MDMA’s reinforcing effects involve enhancement of the rewarding value of social stimuli through interactions between OT and DA circuits (Thompson et al. 2009
). Other studies reporting interactions between social reward and cocaine reward in rats (Thiele et al. 2008
) suggest that interactions between OT and DA may be involved more broadly in addictive behaviors (McGregor et al. 2008
It is also likely that MDMA’s well-described effects on serotonergic (5-HT) signaling play a role in alterations to social processing and behavior. MDMA’s acute pharmacodynamic actions include carrier-mediated release of 5-HT from presynaptic vesicles and monoamine oxidase inhibition, resulting in sudden increases in extracellular 5-HT levels (for review, see Green et al. 2003
). A substantial body of literature implicates 5-HT neurotransmission in social processing and behavior (e.g. Del-Ben et al. 2008
; Young and Leyton, 2002
). Selective 5-HT manipulations alter identification (Del-Ben et al., 2008
) and neural processing of emotional faces (Harmer et al. 2006
), as well as affiliative behavior (Tse and Bond, 2002
). It is unclear to what extent these effects would be expected to overlap with those of MDMA, given that MDMA also affects a range of other systems (see Green et al. 2003
). Future research, perhaps employing pretreatment with selective 5-HT agents, is needed to clarify the role of 5-HT in social effects of MDMA in humans. Individual and interactive effects of 5-HT, OT and DA signaling will provide a rich source for future investigations of MDMA and the neural circuitry underlying social behavior and addiction.
Although these findings suggest that MDMA’s apparently specific effects relate to altered social threat and reward processing, effects of drugs of abuse in general on processing of salient material are poorly understood. It may be that other drugs also exert some of their effects by altering threat and reward processing; indeed, both cannabinoids (Phan et al., 2008
) and alcohol (Gilman et al. 2008
) appear to attenuate social threat responding. To our knowledge, no other drug has been found to increase subjective sociability while both attenuating responses to social threat and increasing social reward responding. However, further research is required to better assess whether other drugs also affect processing of socio-emotionally salient material.
The present findings should be regarded as preliminary; there are a number of limitations remaining to be addressed. The sample was small; these findings require replication in a larger sample. Due to the sample size, we restricted analyses to two a priori
identified brain region; larger samples would facilitate detailed examination of whole brain. Further, MDMA may have actions on cerebral blood flow that affected either global or regionally-specific BOLD signal. Indeed, a previous study employing [H215
O] Positron Emission Tomography (PET) to assess effects of MDMA on regional cerebral blood flow (rCBF) in humans found the drug reduced rCBF in left amygdala, independent of task (Gamma et al. 2000
). Thus, although our interpretation of these findings is supported by their emotion-specific nature, potentially confounding acute effects of MDMA on cerebrovasculature cannot be ruled out. We observed decreased activation with MDMA in both primary visual and motor cortex during a simple motorvisual task, also indicating a need for caution due to the possibility of generalized activation decreases arising from MDMA. However, a global decrease in activation would not give rise to the present finding of increased VS activation to happy versus neutral faces on MDMA. Moreover, decreased visual cortex activation might be expected in the context of decreased amygdala response, given functional connections between the two in processing socially relevant material (Skuse and Gallagher, 2008
For ethical reasons, all participants had prior ecstasy exposure. There was substantial variability in degree and recency of exposure. This may have affected results, as it is possible that heavy ecstasy use causes long-term alterations to serotonergic neurotransmission (McCann et al. 2000
; see also Bedi et al., 2008
for discussion of methodological issues). Moreover, due to involvement of serotonin in vasoconstriction (Cohen et al. 1996
), it is possible that prior or recent MDMA exposure might have affected BOLD responses. To assess this possibility, we examined correlations between extracted BOLD response, lifetime ecstasy use and time since most recent use. There were no correlations between ecstasy-use variables and extracted BOLD signals, suggesting past ecstasy use did not affect results. This may have been because the majority of participants had used MDMA less than 50 times, and were not current users at the time of participation.
For safety reasons, MDMA doses were administered in ascending order, which may have influenced outcomes. In addition, we allowed 6 days between sessions; preclinical findings suggest that in non-human primates serotonin depletion may persist for up to two weeks after single doses (Ricaurte et al. 1988
) or repeated oral doses (Mechan et al. 2005
). Thus, it is possible that a longer period between sessions was required to ensure the absence of carry-over effects. However, although the minimum period between sessions was 6 days, sessions were an average of 10.72 (±7.15) days apart. The doses we employed were substantially less than those used in the primate studies. In addition, assessment of subjective and cardiovascular measures and extracted BOLD signal responses revealed no effect of session order, suggesting that the partial randomization protocol and length of time between sessions did not affect outcomes.
Finally, although the fMRI protocol was designed to coincide with peak drug effects, we did not obtain blood plasma measurements ensuring that imaging data collection coincided with peak plasma MDMA levels. Subjective effects support the timing of the imaging protocol. However, future studies could valuably measure plasma MDMA levels to confirm that imaging data collection coincided with peak plasma MDMA levels. Moreover, assessment of plasma MDMA levels may cast light on the dose-dependency of the sociability-altering effects of MDMA.
Such limitations notwithstanding, these data provide the first evidence that the unusual subjective profile of MDMA may be related to alterations in neural processing of social signals of threat and reward. This possibility has important implications in terms of recreational use and abuse of ecstasy, and potential use of MDMA as a psychotherapeutic agent.