The International Journal of Neuropsychopharmacology

In abstinent MDMA users the cortisol awakening response is off-set but associated with prefrontal serotonin transporter binding as in non-users

Vibe Gedsoe Frokjaera1 c1, David Erritzoea1, Klaus Kähler Holsta1a2, Kathrine Skak Madsena1a3, Patrick MacDonald Fishera1, Jacob Madsena4, Claus Svarera1 and Gitte Moos Knudsena1

a1 Center for Integrated Molecular Brain Imaging and Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Denmark

a2 Department of Biostatistics, University of Copenhagen, Denmark

a3 Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark

a4 PET and Cyclotron Unit, Copenhagen University Hospital, Rigshospitalet, Denmark


Serotonergic signaling is considered critical for an appropriate adaptation to stress. We have previously observed that in healthy volunteers, prefrontal serotonin transporter (SERT) binding is positively associated with hypothalamic-pituitary-adrenal (HPA)-axis output in terms of the cortisol awakening response (CAR). Here, we tested (1) if such a correlation persists in a human model of chronic serotonin depletion, namely in 3,4-Methylenedioxymethamphetamine (MDMA or ‘Ecstasy’) users, and (2) if CAR differed between MDMA users (N = 18) and non-using healthy volunteers (N = 32). Participants underwent SERT brain imaging with [11C]DASB-PET, and performed home-sampling of CAR, defined as the area under curve with respect to cortisol increase from awakening level. When adjusting for age and group, CAR was positively coupled to prefrontal SERT binding (p = 0.006) and MDMA users showed significantly higher CAR than the control group (p = 0.0003). In conclusion, our data confirm the recently described positive association between prefrontal SERT binding and CAR, this time in a human model of serotonin deficiency. Also, we find that CAR was higher in MDMA users relative to non-users. We suggest that the inhibitory control on HPA-axis output is less efficient in the off-balance state established by recent MDMA use, most likely through mechanisms other than those that can be compensated by lowering SERT levels.

(Received October 30 2013)

(Reviewed November 26 2013)

(Revised December 17 2013)

(Accepted January 10 2014)

(Online publication February 14 2014)

Key words

  • Cortisol;
  • DASB;
  • Glucocorticoid;
  • HPA-axis;
  • 5-HTT;
  • MDMA;
  • PET


c1 Address for correspondence: V. G. Frokjaer, Neurobiology Research Unit 9201, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: +45 35456712 Fax: +45 35456713 Email: