“...there is concern that some recreational users of MDMA (particularly those taking high or frequent doses) will also suffer from brain damage.”

MDMA (‘ecstasy’) is a very popular recreational drug with young persons and is a compound that is of interest to experimental pharmacologists, clinical scientists, and also those involved in public health matters, often for related reasons. Pharmacologists and experimental psychologists are interested in MDMA because of the complex effects it can have on serotonin metabolism and function, and they wish to understand the mechanisms involved and link them with the acute and long-term functional effects in both animals and humans. Clinicians and others interested in public health wish to be informed not only about its acute adverse effects when used as a recreational drug but also whether its use will induce any long-term health problems. The fact that many of the behavioral and biochemical effects of the compound which have been observed in human users are also seen when the drug is given to experimental animals means that substantial efforts are being expended in trying to get a greater understanding of its preclinical pharmacological mechanisms of action. The number of publications on this drug has risen sharply over the last 2 to 3 years and the reason the paper is highly cited is because it is arguably the first paper that has tried to review all the major work that has been performed on MDMA: animal studies on pharmacology and behavior, clinical studies on acute and long-term biochemical effects, and also behavioral effects and investigations on drug metabolism.

As a review paper, it cannot be said to present any new discovery or new methodology. However, since the total number of papers on MDMA is still less than 1,000, this paper did provide an opportunity to review essentially all the major preclinical and clinical studies and present them as a coherent whole. Work on MDMA can be emotive, in that results and their interpretation have sometimes been politicized by those eager to present the data as either demonstrating that the drug is extremely toxic, even in a low dose, or safe and having possible clinical usefulness. This review provided the chance to present available data in an unemotional and unbiased way.

The use of MDMA by young persons, particularly when present in the dance club scene, has caused widespread concern because it sometimes results in severe acute adverse events, which can include hyperthermia and even death. These adverse events can also be observed when the drug is given to laboratory animals. In addition, high or repeated doses of MDMA can produce long-term selective damage to serotonin nerve endings in the brains of experimental animals. Therefore there is concern that some recreational users of MDMA (particularly those taking high or frequent doses) will also suffer from brain damage. This would have implications for the future long-term heath of users, given the key role serotonin plays in controlling both normal physiological functions and the control of mood. While there is no unequivocal evidence for impaired serotonin function in the brain of heavy users, some of the indirect evidence does give cause for concern. This review examined both preclinical and clinical data on the effects of MDMA administration, thereby allowing evaluation of all the major studies performed, and the implications of the results obtained for the health of young recreational users.

I have been involved in neuropharmacological research on serotonin since the days of my Ph.D. studies in the late 1960s. MDMA is, therefore, a fascinating drug to me. Not only does it release serotonin in the brain, but it can also be toxic to serotonin nerve endings in the forebrain. While my main work over the last 15 years has been on developing neuroprotective compounds for treating acute ischemic stroke, a comment by a company colleague in 1989 allowed me to follow both interests. He pointed out that the neuroprotective drug MK-801, which is effective in some animal models of stroke, also protected against the long-term neurotoxic damage produced by methamphetamine. I immediately became interested in whether MK-801 and other neuroprotective agents would prevent MDMA-induced neurotoxic damage and also whether the neurochemical mechanisms involved in the damage to the forebrain following MDMA administration were similar to those producing ischemia-induced damage. I was particularly fortunate in that Dr. M. Isabel Colado from Complutense University, Madrid, came to my laboratory in the early 1990s and started working with me on these investigations. She became a good friend and colleague and we have collaborated ever since. Most of my own work on MDMA is performed with colleagues at De Montfort University, Leicester, where I hold an adjunct position.