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Published online before print July 17, 2003

0031-6997/03/5503-463-508$7.00
Pharmacol Rev 55:463-508, 2003

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The Pharmacology and Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy")

A. Richard Green, Annis O. Mechan1, 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.)

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. Effect 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. Effects 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 of 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
The amphetamine derivative (±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a popular recreational drug among young people, particularly those involved in the dance culture. MDMA produces an acute, rapid enhancement in the release of both serotonin (5-HT) and dopamine from nerve endings in the brains of experimental animals. It produces increased locomotor activity and the serotonin behavioral syndrome in rats. Crucially, it produces dose-dependent hyperthermia that is potentially fatal in rodents, primates, and humans. Some recovery of 5-HT stores can be seen within 24 h of MDMA administration. However, cerebral 5-HT concentrations then decline due to specific neurotoxic damage to 5-HT nerve endings in the forebrain. This neurodegeneration, which has been demonstrated both biochemically and histologically, lasts for months in rats and years in primates. In general, other neurotransmitters appear unaffected. In contrast, MDMA produces a selective long-term loss of dopamine nerve endings in mice. Studies on the mechanisms involved in the neurotoxicity in both rats and mice implicate the formation of tissue-damaging free radicals. Increased free radical formation may result from the further breakdown of MDMA metabolic products. Evidence for the occurrence of MDMA-induced neurotoxic damage in human users remains equivocal, although some biochemical and functional data suggest that damage may occur in the brains of heavy users. There is also some evidence for long-term physiological and psychological changes occurring in human recreational users. However, such evidence is complicated by the lack of knowledge of doses ingested and the fact that many subjects studied are or have been poly-drug users.

Address correspondence to: Dr. A. Richard Green, AstraZeneca R&D Charnwood, Loughborough, LE11 5RH, UK. E-mail: richard.green{at}astrazeneca.com




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