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Toxic effect of MDMA on brain serotonin neurons
Letter to the Editor

The Lancet, Vol. 353 (No 9160) April 10, 1999
by Karl Jansen & A.R.W. Forrest

Positron emission tomographic evidence of toxic effect of MDMA ('Ecstasy') on brain serotonin neurons in human beings,
by U. D. McCann; Z Szabo; U Scheffel; R.F. Dannals; G. A. Ricaurte
The Lancet Vol 352, Oct 31, 1998, 1437

Sir--U D McCann and colleagues equate self-reported use of ecstasy with the use of MDMA. Tablets described by users or dealers as ecstasy may contain one or more of various substituted amphetamines, including MDMA, amphetamine, ephedrine, ketamine, tiletamine, or other compounds.2,3 These drugs do not have identical neuropharmacological properties.4 Thus, what these investigators have shown is a difference in serotonin transporter activity between a group of individuals who thought they had taken MDMA in the past, compared with a group of people who said they had never taken MDMA before.

The MDMA users were tested for psychiatric disorders, such as anxiety and depression, and all proved normal. So, these differences in transporter activity relative to the control group existed without any anxiety and depression, as established by the investigators themselves.

Although MDMA may cause some brain changes, the evidence for chronic depression and anxiety disorders as a result of these changes is unconvincing. The midweek mood dip (which usually returns to normal by the end of the week) that follows weekend use of MDMA is due to an acute fall in serotonin, not to structural brain changes.

Were the MDMA users selected entirely at random from all the persons who replied to their advertisements, rather than from a highly selected subsample? None of the 14 cases reported includes people who described taking more than 400 pills. The manner in which the 14 cases seem to have been selected from a large initial sample raises questions about the statistics used. The investigators should clarify their selection procedure.

The statement that the absence of neuropsychiatric disorder means that the low concentrations of transporter could not have been pre-existing is unproven. People with lower concentrations of transporter and other neurochemical differences may experience drives to take drugs of this nature, or to seek stimulation in other ways, without necessarily having a neuropsychiatric disorder. That the participants were tested and proved free from such disorders confirms the point that low serotonin transporter activity can co-exist with a normal mental state.

We believe that it would be valuable to compare serotonin transporter activity in heavy cocaine users with MDMA users. Cocaine is a stimulant that may be sought out by people who might have a pre-existing underactivity of some brain systems, such as parts of the dopamine and serotonin systems. Cocaine is not, however, a ring-substituted amphetamine and does not cause specific changes to serotonin fine terminals. So if heavy cocaine users proved to show similar changes in serotonin transporter mechanisms to MDMA users, we could conclude that these deficits, relative to non-drug use, are pre-existing and not caused by MDMA. We are not convinced that the differences reported by McCann were not pre-existing, because the putative use patterns and doses of MDMA were generally well below those that cause persistent changes in most animal studies. We agree with McCann and colleagues that some people take MDMA at levels equivalent to those used in some animal studies.5

Conclusive proof requires following a group of individuals who continue to use large amounts of MDMA alone, and a comparison of the progression of changes in their serotonin transporter activity with cocaine users and a group of people who do not use drugs.

Karl L R Jansen, *A R W Forrest

South London and Maudsley NHS Trust, at: 13 Ann Moss way, Rotherhithe, London SE16 2TH, U.K.
*Department of Forensic Pathology, University of Sheffield, Sheffield S3 7ER, UK

  1. McCann U, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA. Positron emission tomographic evidence of toxic effect of MDMA ("Ecstasy") on brain serotoninergic neurons in human beings. Lancet 1998; 352: 1433-37.

  2. Milroy CM, Clark JC, Forrest ARW. Pathology of deaths associated with 'ecstasy' and 'eve' misuse. J Clin Pathol 1996; 49: 149-53.

  3. Wolff K, Hay AWM, Sherlock K, Conner M. Contents of "ecstasy". Lancet 1995; 346: 1100-01.

  4. Nichols DE, Marona-Lewicka D, Huang X, Johnson MP. Novel serotonergic agents. Drug Design Discovery 1993; 9: 299-312.

  5. Jansen KLR. Ecstasy (MDMA) dependence. Drug Alcohol Dependence 1998; 53: 121-24.