Effects of MDMA alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin on pupillary light reflex

Psychopharmacology (Berl). 2012 Dec;224(3):363-76. doi: 10.1007/s00213-012-2761-6. Epub 2012 Jun 15.


Rationale: Pupillometry can be used to characterize autonomic drug effects.

Objective: This study was conducted to determine the autonomic effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), administered alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin, on pupillary function.

Methods: Infrared pupillometry was performed in five placebo-controlled randomized studies. Each study included 16 healthy subjects (eight men, eight women) who received placebo-MDMA (125 mg), placebo-placebo, pretreatment-placebo, or pretreatment-MDMA using a crossover design.

Results: MDMA produced mydriasis, prolonged the latency, reduced the response to light, and shortened the recovery time. The impaired reflex response was associated with subjective, cardiostimulant, and hyperthermic drug effects and returned to normal within 6 h after MDMA administration when plasma MDMA levels were still high. Mydriasis was associated with changes in plasma MDMA concentration over time and longer-lasting. Both reboxetine and duloxetine interacted with the effects of MDMA on pupillary function. Clonidine did not significantly reduce the mydriatic effects of MDMA, although it produced miosis when administered alone. Carvedilol and doxazosin did not alter the effects of MDMA on pupillary function.

Conclusions: The MDMA-induced prolongation of the latency to and reduction of light-induced miosis indicate indirect central parasympathetic inhibition, and the faster recovery time reflects an increased sympathomimetic action. Both norepinephrine and serotonin mediate the effects of MDMA on pupillary function. Although mydriasis is lasting and mirrors the plasma concentration-time curve of MDMA, the impairment in the reaction to light is associated with the subjective and other autonomic effects of MDMA and exhibits acute tolerance.

Trial registration: ClinicalTrials.gov NCT00886886 NCT00990067 NCT01136278 NCT01270672 NCT01386177.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agonists / pharmacology
  • Adrenergic Uptake Inhibitors / pharmacology
  • Adrenergic alpha-2 Receptor Agonists / pharmacology
  • Adult
  • Affect / drug effects
  • Autonomic Agents / blood
  • Autonomic Agents / pharmacokinetics
  • Autonomic Agents / pharmacology*
  • Body Temperature Regulation / drug effects
  • Carbazoles / pharmacology*
  • Carvedilol
  • Clonidine / pharmacology*
  • Cross-Over Studies
  • Dopamine Uptake Inhibitors / pharmacology
  • Doxazosin / pharmacology*
  • Duloxetine Hydrochloride
  • Female
  • Hemodynamics / drug effects
  • Humans
  • Light
  • Male
  • Miosis / physiopathology
  • Miosis / prevention & control
  • Morpholines / pharmacology*
  • Mydriasis / chemically induced
  • Mydriasis / physiopathology
  • Mydriatics / blood
  • Mydriatics / pharmacokinetics
  • Mydriatics / pharmacology*
  • N-Methyl-3,4-methylenedioxyamphetamine / blood
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacokinetics
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology*
  • Propanolamines / pharmacology*
  • Randomized Controlled Trials as Topic
  • Reaction Time / drug effects
  • Reboxetine
  • Recovery of Function
  • Reflex, Pupillary / drug effects*
  • Serotonin Uptake Inhibitors / pharmacology
  • Thiophenes / pharmacology*
  • Time Factors
  • Young Adult


  • Adrenergic Agonists
  • Adrenergic Uptake Inhibitors
  • Adrenergic alpha-2 Receptor Agonists
  • Autonomic Agents
  • Carbazoles
  • Dopamine Uptake Inhibitors
  • Morpholines
  • Mydriatics
  • Propanolamines
  • Serotonin Uptake Inhibitors
  • Thiophenes
  • Carvedilol
  • Duloxetine Hydrochloride
  • Reboxetine
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Clonidine
  • Doxazosin

Associated data

  • ClinicalTrials.gov/NCT00886886
  • ClinicalTrials.gov/NCT00990067
  • ClinicalTrials.gov/NCT01136278
  • ClinicalTrials.gov/NCT01270672
  • ClinicalTrials.gov/NCT01386177