The present study is designed to investigate if the popular recreational """"""""designer"""""""" drug of abuse (plus/minus) 3,4-methylenedioxymethamphetamine (MDMA, colloquially known as """"""""Ecstasy"""""""") causes central serotonergic neuronal damage in humans, as it does in a variety of experimental animals, including nonhuman primates. This study will also seek to identify functional consequences of MDMA exposure in a group of human subjects that preliminary data indicate may have sustained serotonergic damage. To ascertain if MDMA does in fact produce serotonergic damage in humans, a cohort of 24 recreational MDMA users (along with an equal number of age and sex matched controls) will be evaluated as follows: First, they will undergo lumbar punctures under carefully standardized experimental conditions to determine if the concentration of 5-hydroxyindoleacetic acid (5HIAA) in their cerebrospinal fluid (CSF) is reduced. On the basis of preclinical studies, it is anticipated that if serotonergic damage has occurred, a decrease in CSF 5HIAA will be observed. Secondly, the same subjects will undergo challenge tests with L- tryptophan. this neuroendocrine test provides a dynamic measure of central serotonergic activity in humans. The prediction is that if recreational MDMA users have sustained serotonergic damage, their rise in prolactin in response to L-tryptophan will be blunted. MDMA subjects will be selected on the basis of (1) self-report of MDMA use corroborated by drug sample analysis (2) no previous history of depression or other neuropsychiatric disease suspected to alter CSF 5HIAA concentration (3) prior agreement to cease using MDMA during the four weeks preceding the study and (4) willingness to be admitted to a clinical research center for detailed testing. Even if CSF and neuroendocrine findings suggest that recreational MDMA users have sustained serotonergic damage, an important question remains. Did MDMA cause the damage, or did other drugs play a role? This difficult question arises because most MDMA users have also experimented with other drugs. To address this issue, a third study will be performed. CSF 5HIAA studies will be carried out in a group of poly- drug users that has not taken MDMA, but is otherwise matched to the MDMA group. If no CSF 5HIAA changes are found in this group, MDMA will be further implicated as a serotonergic neurotoxin in humans. A fourth and final series of experiments will ten evaluate the functional consequences of MDMA exposure. Specifically, it will be determined if recreational MDMA users show disturbances in sleep or other behavioral domains in which serotonin has been implicated. In addition, MDMA subjects will undergo detailed neuropsychological testing to determine if they show evidence of cognitive impairment. The long- term objectives of this research are to better define the public health consequences of recreational MDMA use and to shed light on the role of serotonin in the human central nervous system.
