Effects of MDMA alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin on pupillary light reflex
This study analysed data from five separate clinical trials (n=80) that explored the effects of MDMA on pupillary light reflex and the effects following pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin, respectively. MDMA produced mydriasis, prolonged the latency, reduced the response to light and shortened the recovery time and this impairment returned to normal 6 hours post-treatment. Only reboxetine and duloxetine interacted with the effects of MDMA on pupillary function.
Authors
- Matthias Liechti
- Cédric Hysek
Published
Abstract
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.
Research Summary of 'Effects of MDMA alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin on pupillary light reflex'
Introduction
MDMA (3,4-methylenedioxymethamphetamine) produces marked sympathomimetic effects in humans, including increases in blood pressure, heart rate, body temperature and pupil diameter. Previous laboratory work documented MDMA-induced mydriasis, but it remained unclear whether MDMA alters the pupillary light reflex (dynamic response to a light stimulus), how static and dynamic pupillary changes relate to plasma MDMA exposure and other pharmacodynamic effects, and which adrenergic or serotonergic mechanisms mediate these effects. Hysek and colleagues set out to characterise MDMA effects on both static pupil size and the pupillary light reflex and to probe underlying mechanisms by testing five pharmacological pretreatments. Specifically, they pooled data from five placebo-controlled, double-blind, double-dummy, randomized crossover studies to examine MDMA alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol or doxazosin, with the aims of describing time courses, pharmacokinetic–pharmacodynamic relationships, and interactions with monoaminergic and adrenergic manipulations.
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Study Details
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- APA Citation
Hysek, C. M., & Liechti, M. E. (2012). Effects of MDMA alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin on pupillary light reflex. Psychopharmacology, 224(3), 363-376. https://doi.org/10.1007/s00213-012-2761-6
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References (4)
Papers cited by this study that are also in Blossom
Liechti, M. E., Baumann, C., Gamma, A. et al. · Neuropsychopharmacology (2000)
Liechti, M. E., Gamma, A., Vollenweider, F. X. · Psychopharmacology (2001)
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2010)
Simmler, L. D., Hysek, C. M., Liechti, M. E. · Journal of Clinical Endocrinology Metabolism (2011)
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