An estimated 500,000?,000,000 tablets of 3,4-methylenedioxymethamphetamine (MDMA, or Ecstasy) are taken recreationally each week in England (1). MDMA binds to the serotonin transporter (5-HTT), preventing reuptake and stimulating release of serotonin (5-HT), and causes long-term changes to the 5-HT system in rats, nonhuman primates, and humans (2?A href="#R1623BABDIFDI">4). In view of the critical role of 5-HT in the regulation of mood and the importance of selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depression, it has been suggested that Ecstasy users may be at greater risk for developing affective disturbance following chronic use (5). However, the long-term psychiatric consequences of Ecstasy use are highly controversial (6).

The gene coding for the 5-HTT contains a functional polymorphism in the promoter region, a 44-base-pair insertion/deletion approximately 1 kilobase upstream of the transcription initiator site, designated the 5-HTT gene-linked polymorphic region (5-HTTLPR). This polymorphism produces two alleles, designated l ("long") and s ("short"), respectively (7). Cells with the l allele have been shown to express more 5-HTT than cells with the s allele, and, concordant with this, reuptake of 5-HT in human lymphoblastoid cells homozygous for the l allele has been shown to be approximately twice that of cells either heterozygous or homozygous for the s allele (7).

We investigated Beck Depression Inventory scores and performance on the Affective Go/No-Go test, which is sensitive to emotional processing, in Ecstasy users and comparison subjects. We stratified individuals by 5-HTTLPR genotype, since the 5-HTT is the primary site of action for MDMA and individuals with the s allele are at greater risk for affective disorders (8) and also show poor response to antidepressant treatment with SSRIs (9). We hypothesized that the 5-HTTLPR s allele would confer particular risk for emotionally related cognitive disturbance following Ecstasy use because this allele is associated with lower 5-HTT expression (8) and because experimental animal models of Ecstasy use show increased anxiety and decreased 5-HTT levels (2).