The Pharmacology and Clinical Pharmacology of 3,4-
Methylenedioxymethamphetamine (MDMA, “Ecstasy”)
A. RICHARD GREEN, ANNIS O. MECHAN,1 J. MARTIN ELLIOTT, ESTHER O’SHEA, AND M. ISABEL COLADO
Neuropharmacology Research Centre, School of Pharmacy, De Montfort University, Leicester, United Kingdom (A.R.G., A.O.M., J.M.E.);
AstraZeneca R&D Charnwood, Loughborough, United Kingdom (A.R.G.); and Departamento de Farmacologia, Facultad de Medicina,
Universidad Complutense, Madrid, Spain (E.O., M.I.C.)
0031-6997/03/5503-463–508
PHARMACOLOGICAL REVIEWS Vol. 55, No. 3
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 30304/1082284
Pharmacol Rev 55:463–508, 2003 Printed in U.S.A
Abstract
I. Introduction
II. Epidemiological studies on the use of MDMA
III. Acute effects of MDMA in experimental animals
A. Rats
1. Release and depletion of serotonin in the brain
2. Effect on tryptophan hydroxylase and monoamine oxidase
3. Release and depletion of dopamine in the brain
4. Release and depletion of norepinephrine in the brain
5. Effects on neurotransmitter receptors and transporters
6. Induction of immediate early genes
7. Effects on free radical production in the brain
8. Neuroendocrine and immune responses
9. Cardiovascular and sympathetic effects
10. Body temperature
--a. Effect on body temperature
--b. Pharmacology of the hyperthermic response
--c. Aggregation toxicity
11. Acute behavioral effects—the serotonin syndrome and hyperactivity
12. Effects on motor function tests
13. Anxiety-related behaviors
14. Effects on reinforcement and self-stimulation behavior
15. Effects on cognitive behavior
16. Effects on startle reflexes and prepulse inhibition
B. Mice
1. Effects on monoamine biochemistry in the brain
2. Effects on free radical production in the brain
3. Effects on body temperature
4. Effects on locomotor activity
5. Effects on behavioral tests
C. Nonhuman primates
1. Effects in psychological tests
IV. Long-term effects (neurotoxicity) in experimental animals
A. Rats
1. Evidence for long-term serotonin loss in brain
--a. Biochemical mechanisms
--b. Histology
2. Recovery of serotonin neurochemical markers
3. Effect of central administration of MDMA
4. Effect of preventing acute MDMA-induced hyperthermia
5. Studies on neuroprotection
6. Role of dopamine in the neurodegenerative process
7. Perinatal and early postnatal sensitivity to MDMA
8. Neuronal firing
9. Alterations in serotonin receptor density
10. Long-term functional changes
--a. Behavior
--b. Temperature
--c. Effects on cognitive behavior
--d. Anxiety models
--e. Dopamine
B Mice
1. Long-term dopamine depletion
C. Primates
1. Long-term serotonin depletion and neuronal damage
2. Long-term dopamine depletion and neuronal damage
3. Complex brain function
V. Effects of MDMA in humans
A. Problems in relating animal and human data
1. Doses used
2. Interpreting clinical data
B. Pharmacokinetics of MDMA
C. Acute effects
1. Physiological effects
2. Cerebral blood flow and brain activity
3. Psychological effects
D. Long-term effects
1. Cerebral serotonin
--a. Biochemical studies
--b. Serotonin function
2. Physiological effects
3. Psychological effects
4. Cognitive impairment
5. Cerebral blood flow
VI. Metabolism of MDMA
A. Pathways of metabolism
B. Pharmacology of metabolites
1. 3,4-Methylenedioxyamphetamine
2. Neurotoxicity of other metabolites
VII. Conclusions
Acknowledgments
References
