Stimulants such as methylphenidate (MPH) and modafinil are frequently used as cognitive enhancers in healthy people, whereas 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is proposed to enhance mood and empathy in healthy subjects. However, comparative data on the effects of MPH and modafinil on negative emotions in healthy subjects have been widely missing. The aim of this study was to compare the acute effects of MPH and modafinil on the neural correlates of fearful face processing using MDMA as a positive control.


Using a double-blind within-subject placebo-controlled cross-over design, 60 mg MPH, 600 mg modafinil, and 125 mg MDMA were administrated to 22 healthy subjects, while performing an event-related fMRI task to assess brain activation in response to fearful faces. Negative mood states were assessed with the State-Trait Anxiety Inventory and subjective ratings.


Relative to placebo, modafinil, but not MPH or MDMA, increased brain activation within a limbic-cortical-striatal-pallidal-thalamic circuit during fearful face processing. Modafinil but not MPH also increased amydgala responses to fearful faces compared with MDMA. Furthermore, activation in the middle and inferior frontal gyrus in response to fearful faces correlated positively with subjective feelings of fearfulness and depressiveness after modafinil administration.


In spite of the cognitive enhancement effects of 600 mg modafinil in healthy people, potential adverse effects on emotion processing should be considered.

Schmidt, A., Müller, F., Dolder, P. C., Schmid, Y., Zanchi, D., Egloff, L., … & Borgwardt, S. (2017). Acute effects of methylphenidate, modafinil and MDMA on negative emotion processing. International Journal of Neuropsychopharmacology, pyx112. 10.1093/ijnp/pyx112

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